1-acylpiperidine compounds

ABSTRACT

1-Acylpiperidine compound of the formula I ##STR1## in which R 1  is an optionally substituted aralkyl, aryloxyalkyl, heteroaralkyl, aroyl, heteroaroyl, cycloalkylcarbonyl, aralkanoyl, heteroarylalkanoyl, aralkoxycarbonyl or arylcarbamoyl radical or the acyl radical of an α-amino acid which is optionally N-substituted by lower alkanoyl or carbamoyl-lower-alkanoyl, R 2  is cycloalkyl or an optionally substituted aryl or heteroaryl radical, R 3  is hydrogen, alkyl, carbamoyl or an alkanoyl or alkenoyl radical which is optionally substituted by carboxyl or esterified or amidated carboxyl, R 4  is an optionally substituted aryl or optionally partially hydrogenated heteroaryl radical, X 1  is methylene, ethylene, a direct linkage, an optionally ketalized carbonyl group or an optionally etherified hydroxymethylene group, X 2  is alkylene, carbonyl or a direct linkage, and X 3  is carbonyl, oxo-lower-alkylene, oxo(aza)-lower-alkylene or an alkylene radical which is optionally substituted by phenyl, hydroxymethyl, optionally esterified or amidated carboxyl or, in higher than the α position, by hydroxyl, and its salts have substance-P-antagonistic properties and can be used as pharmaceutically active substances in pharmaceuticals for the treatment of disorders in whose development substance P plays an essential part.

This is a divisional of Ser. No. 08/196,360, filed Apr. 4, 1994 now U.S.Pat. No. 5,541,195, which is a divisional of Ser. No. 07/929,186, filedAug. 11, 1992, now U.S. Pat. No. 5,310,743.

The invention relates to novel 1-acrylpiperidine compounds of theformula I ##STR2## in which R₁ is an optionally substituted aralkyl,aryloxyalkyl, heteroaralkyl, aroyl, heteroaroyl, cycloalkylcarbonyl,aralkanoyl, heteroarylalkanoyl, aralkoxycarbonyl or arylcarbamoylradical or the acyl radical of an α-amino acid which is optionallyN-substituted by lower alkanoyl or carbamoyl-lower-alkanoyl, R₂ iscycloalkyl or an optionally substituted aryl or heteroaryl radical, R₃is hydrogen, alkyl, carbamoyl or an alkanoyl or alkenoyl radical whichis optionally substituted by carboxyl or esterified or amidatedcarboxyl, R₄ is an optionally substituted aryl or optionally partiallyhydrogenated heteroaryl radical, X₁ is methylene, ethylene, a directlinkage, an optionally ketalised carbonyl group or an optionallyetherified hydroxymethylene group, X₂ is alkylene, carbonyl or a directlinkage, and X₃ is carbonyl, oxo-lower-alkylene, oxo(aza)-lower-alkyleneor an alkylene radical which is optionally substituted by phenyl,hydroxymethyl, optionally esterified or amidated carboxyl or, in higherthan the α position, by hydroxyl and their salts, to process for thepreparation of the compounds according to the invention, topharmaceutical products containing these, and to their use aspharmaceutically active substances.

The said aryl, aroyl, aralkanoyl, heteroaryl and heteroaroyl radicalscan be unsubstituted or substituted, such as mono-, di- ortrisubstituted, in particular mono- or disubstituted, for example byaromatically bonded lower alkyl, lower alkoxy, halogen and/ortrifluoromethyl. Aryl, aralkyl, aryloxyalkyl, cycloalkylcarbonyl andaroyl radicals are preferably mono- or disubstituted, such as 3-mono- or3,5-disubstituted, in the stated manner; heteroaryl, heteroaralkyl,heteroaralkanoyl and heteroaroyl radicals are preferably unsubstituted.Aralkyl is, for example, phenyl- or diphenyl-lower-alkyl which isoptionally substituted in the phenyl or naphthyl moiety.

Aryloxy-lower-alkyl is, for example, phenoxy-lower-alkyl which isoptionally substituted in the phenyl moiety.

Heteroalkyl is, for example, heteroaryl-lower-alkyl which has asheteroaryl radical aza-heteroaryl which is 6-membered and monocyclic oris bicyclic and composed of a 6-membered and a 5- or 6-membered ring.

Aroyl is, for example, optionally substituted benzoyl such as benzoyl,3-lower-alkyl-, 3-lower-alkoxy-, 3-halogeno-, 3-dimethylamino-,3,5-di-lower-alkyl, 3,5-di-lower-alkoxy-, 3,5-dihalogeno- or3,5-ditrifluoromethylbenzoyl, or secondarily optionally substitutednaphthoyl such as 1- or 2-naphthoyl.

Heteroaroyl is, for example, aza-heteroaroyl which is 6-membered andmonocyclic or is bicyclic and composed of a 6-membered and a 5- or6-membered ting, such as pyridylcarbonyl or quinolinylcarbonyl.

Cycloalkylcarbonyl is, for example, optionally substituted 3- to 8-, inparticular 5- to 7-membered, cycloalkylcarbonyl such ascyclohexylcarbonyl, 3-lower-alkyl-, 3-lower-alkoxy-, 3-halogeno-,3-dimethylamino-, 3,5-di-lower-alkyl, 3,5-di-lower-alkoxy-,3,5-dihalogeno- or 3,5-ditrifluoromethylcyclohexylcarbonyl.

Aralkanoyl means, for example, phenyl- or diphenyl-lower-alkanoyl whichis optionally substituted in the phenyl moiety.

Heteroarylalkanoyl is, for example, heteroaryl-lower-alkanoyl which hasas heteroaryl radical aza-heteroaryl which is 6-membered and monocyclicor is bicyclic and composed of a 6-membered and a 5- or 6-membered ring.

Arylcarbamoyl means, for example, N-phenylcarbamoyl which isunsubstituted or optionally substituted in the phenyl moiety.

Acyl radicals of optionally N-alkanoylated α-amino acids are derived, inparticular, from α-amino acids which occur in nature as building blocksof peptides and are optionally lower-alkanoylated, for example N-C₂ -C₇alkanoylated, such as substituted by acetyl, propionyl, butyryl orpivaloyl. Examples are groups of the formula ##STR3## in which R₅ ishydrogen, or a lower alkyl radical which is optionally substituted byhydroxyl, amino, mercapto, optionally hydroxyl-substituted phenyl,carboxyl, carbamoyl or ureido, such as C₁ -C₄ alkyl radical, for examplemethyl, isopropyl, isobutyl, secondary butyl, hydroxymethyl,mercaptomethyl, 2-methylmercaptoethyl, 3-ureidopropyl, 4-aminobutyl,carboxymethyl, carbamoylmethyl, 2-carboxyethyl, 2-carbamoylethyl, benzylor 4-hydroxybenzyl, and R₆ is lower alkanoyl, for example C₂ -C₇alkanyol, such as acetyl, propionyl, butyryl or pivaloyl. However, itcan also be the acryl group of a heterocyclic α-amino acid which occursnaturally as building blocks of peptides, such as prolyl, tryptophanylor histidinyl.

Cycloalkyl is, for example, 5- to 7-membered cycloalkyl such as, inparticular, cyclohexyl or secondarily cyclopentyl or cycloheptyl.

Aryl is, for example, phenyl or, in particular as R₄, naphthyl.

Heteroaryl is, for example, 6-membered monocyclic aza-heteroaryl such aspyridyl, or, as R₄ in particular heteroaryl which is composed of anoptionally partially hydrogenareal 5- or 6-membered mono- or diaza- oroxa-heteroaryl radical and of a 6-membered aryl radical, such asbenzofuranyl, for example benzofuran-2-yl or -3-yl, indolyl, for exampleindol-2-yl or -3-yl, 2,3-dihydroindolyl, for example2,3-dihydroindol-2-yl or -3-yl, benzimidazolyl, for examplebenzimidazol-2-yl, quinolyl, for example quinolin-4-yl, or1,2,3,4-teurahydroquinolin-4-yl.

As heteroaryl radical of heteroaryl-lower-alkanoyl which hasaza-heteroaryl which is 6-membered and monocyclic or is bicyclic andcomposed of a 6-membered and 5- or 6-membered ring is, for example,corresponding heteroaryl-C₁ -C₄ alkanoyl, such as 2-pyridyl- or4-pyridylacetyl, 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-3-ylcarbonyl.

Alkyl is, in particular, lower alkyl; alkylene in particular loweralkylene.

Ketalised carbonyl groups are, for example, ketalised with an aliphaticalcohol or a dialcohol such as with a lower alkanol or a loweralkanediol and are, for example, di-lower-alkoxymethylene or loweralkylenedioxymethylene.

Etherified hydroxymethylene is, in particular, etherified with analiphatic alcohol such as a lower alkanol and is, for example, loweralkoxymethylene.

Optionally esterified or amidated carboxyl is, for example, carboxyl,lower alkoxycarbonyl, carbamoyl or N-mono- orN,N-di-lower-alkylcarbamoyl.

Alkanoyl or alkenoyl radicals which are optionally substituted bycarboxyl or esterified or amidated carboxyl are, for example, loweralkanoyl such as C₂ -C₇ alkanoyl such as acetyl, propionyl, butyryl orpivaloyl, carboxy-lower-alkanoyl such as carboxy-C₃ -C₇ alkanoyl such assuccinoyl, glutaroyl or adipoyl, or carboxy-lower-alkenoyl such ascarboxy-C₃ -C₅ alkenoyl such as maleyl, fumaroyl or tartroyl, in whichcarboxyl can also be esterified or amidated, and, for example, loweralkoxycarbonyl such as C₁ -C₄ alkoxycarbonyl, for example methoxy- orethoxycarbonyl, carbamoyl or N-mono- or N,N-di-lower-alkylcarbamoyl suchas N-mono- or N,N-di-C₁ -C₄ alkylcarbamoyl, for example N-methyl- orN,N-dimethylcarbamoyl.

Lower alkylene substituted in higher than the α position by hydroxyl is,for example, hydroxylated in position 2 with respect to the N atom.

Lower alkylene substituted by hydroxymethyl or optionally esterified oramidated carboxyl is, for example, substituted in position 1, 2 or,where present, 3 with respect to the N atom by carboxyl, loweralkoxycarbonyl, carbamoyl, N-mono- or N,N-di-lower-alkylcarbamoyl orhydroxymethyl.

Hereinbefore and hereinafter lower radicals and compounds are to beunderstood to be, for example, those which have up to and including 7,preferably up to and including 4, carbon atoms (C atoms).

Lower alkyl is, for example, C₁ -C₇ alkyl, preferably C₁ -C₄ alkyl, suchas, in particular, methyl or secondarily ethyl, propyl, isopropyl orbutyl, but can also be isobutyl, secondary butyl, tertiary butyl or a C₅-C₇ alkyl such as pentyl, hexyl or heptyl group.

Lower alkylene is, for example, C₁ -C₇ alkylene, preferably C₁ -C₄alkylene such as methylene, ethylene, 1,3-propylene, 1,4-butylene or1,5-pentylene.

Phenyl or diphenyl-lower-alkyl which is optionally substituted in thephenyl is, for example, corresponding phenyl- or diphenyl-C₁ -C₄ alkylsuch as benzyl, 2,4-dichlorobenzyl, 3,5-ditrifluoromethylbenzyl,2-phenylethyl or 2,2-diphenylethyl.

Phenyl- or diphenyl-lower-alkanoyl which is optionally substituted inthe phenyl moiety is, for example, corresponding phenyl- or diphenyl-C₁-C₄ alkanoyl such as 2,2-diphenylacetyl or 2,3-diphenylpropionyl.

Phenoxy-lower-alkyl which is optionally substituted in the phenyl is,for example, phenoxy-C₁ -C₄ alkyl which is substituted by halogen and/ortriazolyl, such as 2-[2-(1H-1,2,4-triazol-1-yl)-4-chlorophenoxy]ethyl.

As heteroaryl radical of heteroaryl-lower-alkyl which has aza-heteroarylwhich is 6-membered and monocyclic or is bicyclic and composed of a6-membered and a 5- or 6-membered ring is, for example, pyridyl- orquinolinyl-C₁ -C₄ alkyl such as 4-quinolinylmethyl.

Lower alkoxy is, for example, C₁ -C₇ alkoxy, preferably C₁ -C₄ alkoxy,such as methoxy, ethoxy, propyloxy, isopropyloxy or butyloxy, but canalso be isobutyloxy, secondary butyloxy, tertiary butyloxy or apentyloxy, hexyloxy or heptyloxy group.

Halogen is, for example, halogen of atomic number up to and including35, such as chlorine or fluorine, furthermore bromine.

Lower alkoxycarbonyl is, for example, C₁ -C₇ alkoxycarbonyl, preferablyC₁ -C₄ alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl,propyloxycarbonyl, isopropyloxycarbonyl or butyloxycarbonyl, but canalso be isobutyloxycarbonyl, secondary butyloxycarbonyl, tertiarybutyloxycarbonyl or a pentyloxycarbonyl, hexyloxycarbonyl orheptyloxycarbonyl group.

N-lower-alkylcarbamoyl is, for example, N-C₁ -C₇ alkylcarbamoyl,preferably N-C₁ -C₄ alkylcarbamoyl, such as methylcarbamoyl,ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl or butylcarbamoyl,but can also be isobutylcarbamoyl, secondary butylcarbamoyl, tertiarybutylcarbamoyl or a pentylcarbamoyl, hexylcarbamoyl or heptylcarbamoylgroup.

N,N-di-lower-alkylcarbamoyl is, for example, N,N-di-C₁ -C₇alkylcarbamoyl, preferably N,N-di-C₁ -C₄ alkylcarbamoyl, such asN,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-ethyl-N-methylcarbamoyl,N,N-dipropylcarbamoyl, N-methyl-N-propylcarbamoyl,N-isopropyl-N-methylcarbamoyl or N-butyl-N-methylcarbamoyl, but can alsobe N-isobutyl-N-methylcarbamoyl, N-methyl-N-secondary butylcarbamoyl,N-methyl-N-tertiary butylcarbamoyl or a N-methyl-N-pentylcarbamoyl,N-hexyl-N-methylcarbamoyl or N-heptyl-N-methylcarbamoyl group.

Lower alkylene which is substituted in higher than the α position and inlower than the ω position by hydroxyl is, for example,1,3-(2-hydroxy)propylene, 1,4-(2-hydroxy)butylene,1,4-(3-hydroxy)butylene, 1,5-(2-hydroxy)pentylene1,5-(3-hydroxy)pentylene or 1,5-(4-hydroxy)pentylene.

Lower alkylene substituted by carboxyl is, for example,carboxymethylene, 1- or 2-carboxyethylene, 1,3-(2-carboxy)propylene,1,4-(2-carboxy)butylene, 1,4-(3-carboxy)butylene,1,5-(2-carboxy)pentylene 1,5-(3-carboxy)pentylene or1,5-(4-carboxy)pentylene.

Lower alkylene substituted by lower alkoxycarbonyl is, for example,lower alkoxycarbonylmethylene, 1- or 2-lower-alkoxycarbonylethylene,1,3-(2-lower-alkoxycarbonyl)propylene,1,4-(2-lower-alkoxycarbonyl)butylene,1,4-(3-lower-alkoxycarbonyl)butylene,1,5-(2-lower-alkoxycarbonyl)pentylene1,5-(3-lower-alkoxycarbonyl)pentylene or1,5-(4-lower-alkoxycarbonyl)pentylene, where lower alkoxycarbonyl meansin each case, for example, C₁ -C₄ alkocycarbonyl, such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl.

Lower alkylene substituted by carbamoyl, N-mono- orN,N-di-lower-alkylcarbamoyl is, in particular, substituted by carbamoyland means, for example, carbamoylmethylene, 1- or 2-carbamoylethylene,1,3-(2-carbamoyl)propylene, 1,4-(2-carbamoyl)butylene,1,4-(3-carbamoyl)butylene, 1,5-(2-carbamoyl)pentylene,1,5-(3-carbamoyl)pentylene or 1,5-(4-carbamoyl)pentylene.

Lower alkylene substituted by hydroxymethyl is, for example,2-hydoxyethylidene, 2,3-(1-hydroxy)propyl1,3-(2-hydroxymethyl)propylene, 2,4-(1-hydroxy)butylene,1,4-(2-hydroxymethyl)butylene, 1,4-(3-hydroxymethyl)butylene,1,5-(2-hydroxymethyl)pentylene 1,5-(3-hydroxymethyl)pentylene or1,5-(4-hydroxymethyl)pentylene.

Lower alkoxymethylene is, for example, C₁ -C₄ alkoxymethylene such asmethoxymethylene, ethoxymethylene, propyloxymethylene orbutyloxymethylene.

Di-lower-alkoxymethylene is, for example, di-C₁ -C₄ alkoxymethylene suchas dimethoxymethylene, diethoxymethylene, dipropyloxymethylene ordibutyloxymethylene.

Lower alkylenedioxymethylene is, for example, 5- to 8-membered, inparticular 5- or 6-membered 1,3-dioxacycloalk-2-yl, such as1,3-dioxacyclobut-2-yl, 1,3-dioxacyclopent-2-yl (1 ,3-dioxolan-2-yl),1,3-dioxacyclohex-2-yl (1 ,3-dioxan-2-yl) or 1,3-dioxacyclohept-2-yl.

The compounds of the formula I have basic or, where R₃ and/or X₃ issubstituted by carboxyl, amphoteric characteristics and can accordinglyform acid addition salts and, where appropriate, inner salts.

Acid addition salts of compounds of the formula I are, for example,their pharmaceutically utilisable salts with suitable mineral acids suchas hydrohalic acids, sulfuric acid or phosphoric acid, for examplehydrochlorides, hydrobromides, sulfates, hydrogensulfates or phosphates,or salts with suitable aliphatic or aromatic sulfonic acids orN-substituted sulfamic acids, for example methanesulfonates,benzenesulfonates, p-toluenesulfonates or N-cyclohexylsulfamates(cyclamates).

It is also possible to use pharmaceutically unsuitable salts forisolation or purification. Only the pharmaceutically utilisablenon-toxic salts are used therapeutically and they are thereforepreferred.

The compounds prepared according to the invention have valuablepharmacological properties. In particular, they show a pronouncedantagonistic action against substance P and display the spectrum ofproperties typical of substance P antagonists. Thus, the compounds ofthe formula I and their pharmaceutically utilisable salts completelyinhibit in vitro the binding of ³ H-substance P to the bovine retina inthe radioreceptor assay of H. Bittiger, Ciba Foundation Symposium91,196-199 (1982) in concentrations from about 10 μ-mol/L. In vivo, theyinhibit, from a dose of about 0.01 mg/kg i.v., the vasodilatationinduced by substance P, measured on the guinea pig ear based on theexperimental design of Andrews and Helme, Regul. Pept. 25, 267-275(1989) and, from a dose of about 1.0 mg/kg i.v., based on theexperimental design of Lundberg et al, Proc. Nat. Acad. Sci. (U.S.A.)80, 1120-1124 vagally induced bronchospasms in the guinea pig, whichindicates their suitability for the treatment of asthma. Theirutilisability for the treatment of disorders of the central nervoussystem is indicated, for example, by their inhibitory effect on thechange in behaviour induced by icv-applied substance P methyl ester inthe gerbil according to A. Vassout et al., Meeting on Substance P,Worcester, Mass. (1990) with an ED₅₀ from about 10 mg/kg s.c., fromabout 30 mg/kg i.p. and from about 100 mg/kg p.o.

Substance P is a naturally occurring undecapeptide of the tachykininfamily. It is produced in the mammalian body and acts pharmacologicallyas neuropeptide. Substance P plays an essential role in variousdisorders, for example in conditions of pain, in migraine and in somedisorders of the central nervous system, such as in anxiety states,schizophrenia and depression, as well as in certain movement disorders,such as in Parkinson's disease, but also in inflammatory disorders suchas in rheumatoid arthritis, iritis and conjunctivitis, in disorders ofthe respiratory organs such as in asthma and chronic bronchitis, indisorders of the gastrointestinal system, such as in ulcerative colitisand Crohn's disease, and in hypertension.

There has therefore been no lack of attempts to develop substance Pantagonists. However, a series of the substance P antagonists disclosedto date are peptidic compounds which are too metabolically labile to beemployed as pharmaceutically active substances.

The substance P antagonists, prepared according to the invention, of theformula I and their pharmaceutically utilisable salts are, by contrast,metabolically stable and accordingly outstandingly suitable for thetherapeutic treatment of the said disorders.

The invention primarily relates to compounds of the formula I in whichR₁ is a phenyl-, diphenyl-, naphthyl- or fluorenyl-lower-alkyl radicalwhich is unsubstituted or substituted in the phenyl moiety by loweralkyl, lower alkoxy, di-lower-alkylamino, halogen and/ortrifluoromethyl, a phenoxy-lower-alkyl radical which is unsubstituted orsubstituted in the phenyl moiety by halogen and/or triazolyl, aheteroaryl-lower-alkyl radical which has as heteroaryl radicalaza-heteroaryl which is 6-membered and monocyclic or is bicyclic andcomposed of a 6-membered and a 5- or 6-membered ring, a benzoyl,naphthoyl fluorenoyl or 3- to 8-membered cycloalkylcarbonyl radicalwhich is unsubstituted or substituted by lower alkyl, lower alkoxy,hydroxyl, di-lower-alkylamino, halogen, cyano and/or trifluoromethyl, aphenyl- or diphenyl-lower-alkanoyl radical which is unsubstituted orsubstituted in the phenyl moiety by lower alkyl, lower alkoxy,di-lower-alkylamino, halogen and/or trifluoromethyl, aheteroaryl-lower-alkanoyl radical which has as heteroaryl radicalaza-heteroaryl which is 6-membered and monocyclic or is bi- or tricyclicand composed of a 6-membered and one or two 5- or 6-membered ring(s), aphenyl-lower-alkoxycarbonyl or N-phenylcarbamoyl radical which isunsubstituted or substituted in the phenyl moiety by lower alkyl, loweralkoxy, di-lower-alkylamino, halogen and/or trifluoromethyl, or the acylradical of an α-amino acid which occurs in nature as peptide buildingblock and is optionally N-substituted by lower alkanoyl orcarbamoyl-lower-alkanoyl, R₂ is 5- to 7-membered cycloalkyl or a phenyl,naphthyl or 6-membered monocyclic aza-heteroaryl radical which isunsubstituted or substituted by aromatically bonded lower alkyl, loweralkoxy, halogen and/or trifluoromethyl, R₃ is hydrogen, lower alkyl,carbamoyl, lower alkanoyl, carboxy-lower-alkanoyl orcarboxy-lower-alkenoyl, lower alkoxycarbonyl-lower-alkyl,carbamoyl-lower-alkanoyl, N-mono- orN,N-di-lower-alkylcarbamoyl-lower-alkanoyl,N-cyclalkylcarbamoyl-lower-alkanoyl or N-phenylcarbamoyl-lower-alkanoyl,R₄ is a phenyl, naphthyl or pyridyl radical which is unsubstituted orsubstituted by lower alkyl, lower alkoxy, halogen and/ortrifluoromethyl, or a heteroaryl radical which is unsubstituted orC-substituted by lower alkyl, lower alkoxy, halogen and/ortrifluoromethyl and optionally N-substituted by lower alkanoyl and iscomposed of an optionally partially hydrogenated 5- or 6-membered mono-or diaza- or oxa-heteroaryl radical and a 6-membered aryl radical, X₁ ismethylene, ethylene, a carbonyl group which is optionally ketalised witha lower alkanol or a lower alkanediol, a hydroxymethylene group which isoptionally etherified with a lower alkanol, or a direct linkage, X₂ iscarbonyl, lower alkylene or a direct linkage, and X₃ is carbonyl,oxo-lower-alkylene, oxo(aza)-lower-alkylene or a lower alkylene radicalwhich is unsubstituted or substituted by phenyl or in the 1, 2 or, wherepresent, 3 position with respect to the N atom by carboxyl, loweralkoxycarbonyl, carbamoyl, N-mono- or N,N-di-lower-alkylcarbamoyl orhydroxymethyl, and the salts thereof.

The invention particularly relates to compounds of the formula I inwhich R₁ is phenyl- or diphenyl-C₁ -C₄ alkyl which is unsubstituted orsubstituted in the phenyl moiety by lower alkyl, lower alkoxy,di-lower-alkylamino, halogen and/or trifluoromethyl, such as benzyl,2,4-dichlorobenzyl, 3,5-ditrifluoromethylbenzyl, 2-phenylethyl or2,2-diphenylethyl, phenoxy-C₁ -C₄ alkyl which is unsubstituted orsubstituted in the phenyl by halogen and/or triazolyl, pyridyl- orquinolinyl-C₁ -C₄ alkyl, such as 4-quinolinylmethyl, benzoyl which isunsubstituted or substituted by lower alkyl, lower alkoxy,di-lower-alkylamino, halogen and/or trifluoromethyl, such as benzoyl,3-lower-alkyl-, 3-lower-alkoxy-, 3-halogeno-, 3-dimethylamino-,3,5-di-lower-alkyl, 3,5-di-lower-alkoxy-, 3,5-dihalogeno- or3,5-ditrifluoromethylbenzoyl, or secondarily naphthoyl which isunsubstituted or substituted by lower alkyl, lower alkoxy,di-lower-alkylamino, halogen and/or trifluoromethyl, such as 1- or2-naphthoyl, pyridylcarbonyl or quinolinylcarbonyl which isunsubstituted or substituted by lower alkyl, lower alkoxy, halogenand/or trifluoromethyl, 5- to 7-membered cycloalkylcarbonyl which isunsubstituted or substituted by lower alkyl, lower alkoxy,di-lower-alkylamino, halogen and/or trifluoromethyl, such ascyclohexylcarbonyl, 3-methyl-, 3-methoxy-, 3-chloro-, 3-dimethylamino-,3,5-dmethyl-, 3,5-dimethoxy-, 3,5-dichloro or3,5-ditrifluoromethylcyclohexylcarbonyl, phenyl- or diphenyl-C₁ -C₄alkanoyl which is unsubstituted or substituted in the phenyl by loweralkyl, lower alkoxy, di-lower-alkylamino, halogen and/ortrifluoromethyl, such as 2,2-diphenylacetyl or 2,3-diphenylpropionyl,N-phenylcarbamoyl which is unsubstituted or optionally substituted inthe phenyl moiety by lower alkyl, lower alkoxy, di-lower-alkylamino,halogen and/or trifluoromethyl, or a group of the formula Ia ##STR4## inwhich R₅ is hydrogen, C₁ -C₄ alkyl which is unsubstituted or substitutedby hydroxyl, mercapto, amino, optionally hydroxy-substituted phenyl,carboxyl, carbamoyl or ureido, and R₆ is C₂ -C₇ alkanoyl, R₂ is 5- to7-membered cycloalkyl or a phenyl, naphthyl or pyridyl radical which isunsubstituted or substituted by C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halogenand/or trifluoromethyl, R₃ is hydrogen, C₁ -C₇ alkyl, carbamoyl, C₂ -C₇alkanoyl, carboxy-C₁ -C₄ alkanoyl or carboxy-C₂ -C₄ alkenoyl, R₄ isphenyl or naphthyl which is unsubstituted or substituted by C₁ -C₄alkyl, C₁ -C₄ alkoxy, halogen and/or trifluoromethyl, or unsubstitutedpyridyl, benzofuranyl, indolyl, 2,3-dihydroindolyl, benzimidazolyl,quinolyl or 1,2,3,4-tetrahydroquinolinyl, X₁ is methylene,hydroxymethylene, C₁ -C₄ alkoxymethylene, carbonyl, di-C₁ -C₄alkoxymethylene or a direct linkage, X₂ is C₁ -C₇ alkylene, carbonyl ora direct linkage, and X₃ is carbonyl, C₁ -C₄ alkylene, carboxy-C₁ -C₄alkylene, C₁ -C₄ alkoxycarbonyl-C₁ -C₄ alkylene, carbamoyl-C₁ -C₄alkylene or hydroxymethyl-C₁ -C₄ alkylene and the salts thereof.

The invention particularly relates to compounds of the formula I inwhich R₁ is benzoyl, naphthoyl or phenyl-C₁ -C₄ alkanoyl which isunsubstituted or substituted by C₁ -C₄ alkyl, such as methyl, C₁ -C₄alkoxy, such as methoxy, halogen and/or trifluoromethyl, unsubstitutedpyridylcarbonyl or quinolinylcarbonyl or a group of the formula Ia##STR5## in which R₅ is hydrogen, C₁ -C₄ alkyl which is unsubstituted orsubstituted by hydroxyl, mercapto, amino, optionally hydroxy-substitutedphenyl, carboxyl, carbamoyl or ureido, for example methyl, isopropyl,isobutyl, secondary butyl, hydroxymethyl, mercaptomethyl,2-methylmercaptoethyl, 3-ureidopropyl, 4-aminobutyl, carboxymethyl,carbamoylmethyl, 2-carboxyethyl, 2-carbamoylethyl, benzyl or4-hydroxybenzyl, and R₆ is C₂ -C₇ alkanoyl, such as acetyl, propionyl,butyryl or pivaloyl, R₂ is 5- to 7-membered cycloalkyl, especiallycyclohexyl or secondarily cyclopentyl or cycloheptyl, or a phenyl,naphthyl or pyridyl radical which is unsubstituted or substituted by C₁-C₄ alkyl, such as methyl, C₁ -C₄ alkoxy, such as methoxy, halogenand/or trifluoromethyl, R₃ is hydrogen, C₁ -C₇ alkyl, such as methyl,ethyl, propyl, isopropyl or butyl, isobutyl, secondary butyl or tertiarybutyl, carbamoyl, C₁ -C₇ alkanoyl such as acetyl, propionyl, butyryl orpivaloyl, carboxy-C₁ -C₄ alkanoyl such as succinoyl, glutaroyl oradipoyl, or carboxy-C₃ -C₅ alkenoyl such as maleyl, fumaroyl ortartroyl, R₄ is phenyl or naphthyl which is unsubstituted or substitutedby C₁ -C₄ alkyl, such as methyl, C₁ -C₄ alkoxy, such as methoxy, halogenand/or trifluoromethyl, or unsubstituted pyridyl, benzofuranyl, indolyl,benzimidazolyl or quinolyl, X₁ is methylene, hydroxymethylene, C₁ -C₄alkoxymethylene such as methoxymethylene, ethoxymethylene,propyloxymethylene or butyloxymethylene, carbonyl, di-C₁ -C₄alkoxymethylene such as dimethoxymethylene, diethoxymethylene,dipropyloxymethylene or dibutyloxymethylene, or a direct linkage, X₂ isC₁ -C₇ alkylene such as methylene or secondarily ethylene or1,3-propylene, carbonyl or a direct linkage, and X₃ is carbonyl, C₁ -C₄alkylene, such as methylene, ethylene or or 1,3-propylene, carboxy-C₁-C₄ alkylene such as 1,3-(2-carboxy)propylene, 1,4-(2-carboxy)butylene,1,4-(3-carboxy)butylene, C₁ -C₄ alkoxycarbonyl-C₁ C₄ alkylene, such as1,3-(2-C₁ -C₄ alkoxycarbonyl)propylene, 1,4-(2-C₁ -C₄alkoxycarbonyl)butylene, 1,4-(3-C₁ -C₄ alkoxycarbonyl)butylene,1,5-(2-C₁ -C₄ alkoxycarbonyl)pentylene 1,5-(3-C₁ -C₄alkoxycarbonyl)pentylene or 1,5-(4-C₁ -C₄ alkoxycarbonyl)pentylene,where C₁ -C₄ alkoxycarbonyl means in each case, for example,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl,carbamoyl-C₁ -C₄ alkylene such as 1,3-(2-carbamoyl)propylene,1,4-(2-carbamoyl)butylene, 1,4-(3-carbamoyl)butylene,1,5-(2-carbamoyl)pentylene, 1,5-(3-carbamoyl)pentylene or1,5-(4-carbamoyl)pentylene, or hydroxymethyl-C₁ -C₄ alkylene such as1,3-(2-hydroxymethyl)propylene, 1,4-(2-hydroxymethyl)butylene,1,4-(3-hydroxymethyl)butylene, 1,5-(2-hydroxymethyl)pentylene1,5-(3-hydroxymethyl)pentylene or 1,5-(4-hydroxymethyl)pentylene, andthe salts thereof.

The invention preferably relates to compounds of the formula I in whichR₁ is benzoyl which is unsubstituted or mono- or disubstituted by C₁ -C₄alkyl, such as methyl, C₁ -C₄ alkoxy, such as methoxy, halogen of atomicnumber up to and including 35, such as chlorine, and/or trifluoromethyl,or unsubstituted naphthoyl or phenyl-C₁ -C₄ alkanoyl, R₂ is phenyl whichis unsubstituted or mono- or disubstituted by C₁ -C₄ alkyl, such asmethyl, C₁ -C₄ alkoxy, such as methoxy, halogen of atomic number up toand including 35, such as chlorine, and/or trifluoromethyl, orunsubstituted pyridyl, R₃ is hydrogen, C₁ -C₄ alkyl such as methyl,ethyl, propyl, or isopropyl, carbamoyl or C₂ -C₇ alkanoyl such asacetyl, propionyl, butyryl or pivaloyl, R₄ is phenyl which isunsubstituted or mono- or disubstituted by C₁ -C₄ alkyl, such as methyl,C₁ -C₄ alkoxy, such as methyl, halogen of atomic number up to andincluding 35, such as chlorine, and/or trifluoromethyl, or unsubstitutednaphthyl, pyridyl, benzofuranyl, indolyl, benzimidazolyl or quinolyl, X₁is methylene, hydroxymethylene, carbonyl or a direct linkage, X₂ is adirect linkage, and X₃ is C₁ -C₄ alkylene, such as methylene orsecondarily ethylene or 1,3-propylene, and the salts thereof.

The invention relates above all to compounds of the formula I in whichR₁ is benzoyl which is unsubstituted or mono- or disubstituted by C₁ -C₄alkyl such as methyl, C₁ -C₄ alkoxy such as methoxy, halogen of atomicnumber up to and including 35 such as chlorine and/or trifluoromethyl,or unsubstituted naphthoyl, R₂ is unsubstituted phenyl or phenyl mono-or disubstituted by halogen of atomic number up to and including 35 suchas chlorine and/or trifluoromethyl, R₃ is hydrogen, R₄ is unsubstitutedquinolinyl, X₁ is methylene, X₂ is a direct linkage, and X₃ is C₁ -C₄alkylene such as methylene or secondarily ethylene or 1,3-propylene, andto the salts thereof.

The invention especially relates to the compounds of the formula I, andthe salts thereof, specified in the examples.

The invention furthermore relates to a process, which is based onmethods known per se, for the preparation of the compounds according tothe invention. This is characterised in that

a) the radical R₁ is introduced into a compound of the formula II##STR6## in which R₂, R₃, R₄, X₁, X₂ and X₃ have the indicated meanings,or

b) compounds of the formulae III and IV ##STR7## in which Y₁ is a groupof the formula --N(R₃)--H and Y₂ is hydroxyl, reactive esterifiedhydroxyl or, if X₃ is carbonyl, is etherified hydroxyl, or Y₁ ishydroxyl, reactively esterified hydroxyl or, if X₂ is carbonyl, isetherified hydroxyl and Y₂ is a group of the formula --N(R₃)--H, whereR₂, R₃, R₄, X₁, X₂ and X₃ have the indicated meanings, or the saltsthereof, are condensed together or

c) for the preparation of compounds of the formula I in which one of theradicals X₂ and X₃ is alkylene and the other is alkylene, carbonyl or,in the case of X₂, a direct linkage or, in the case of X₃, an alkyleneradical which is optionally substituted by hydroxymethyl or optionallyesterified or amidated carboxyl, in a compound of the formula V ##STR8##in which Z₁ is an alkylene radical which is substituted by oxo orhydroxyl in the α position to the group --N(R₃)--, and Z₂ is alkylene,carbonyl or an alkylene radical which is optionally substituted byhydroxymethyl or optionally esterified or amidated carboxyl, or Z₁ isalkylene, carbonyl or a direct linkage and Z₂ is alkylene radicalsubstituted by oxo or hydroxyl in the α position to the group --N(R₃)--,and R₂, R₃, R₄, X₁, X₂ and X₃ have the indicated meanings, or in a saltthereof, the oxo or hydroxyl group in the α position to the group--N(R₃)-- is replaced by hydrogen by reduction, or in a compound of theformula VI ##STR9## in which Z₃ is a radical of the formula--C(R_(a))═C(R_(b))-- and Z₄ is alkylene, carbonyl or an alkyleneradical which is optionally substituted by hydroxymethyl or optionallyesterified or amidated carboxyl, or Z₃ is alkylene, carbonyl or a directlinkage and Z₄ is a radical of the formula --C(R_(a))═C(R_(b))--, whereR_(a) and R_(b) are each hydrogen or lower alkyl, the radical of theformula --C(R_(a))═C(R_(b))-- is reduced by reduction of the double bondto the corresponding radical --CH(R_(a))--CH(R_(b))--, or

d) for the preparation of compounds of the formula I in which X₁ is acarbonyl or hydroxymethylene group, compounds of the formulae VII andVIII ##STR10## in which one of the radicals Y₃ and Y₄ is formyl or anoptionally anhydridised or esterified carboxyl group and the other is ametallic radical, and R₂, R₃, R₄, X₂ and X₃ have the indicated meanings,are condensed together or

e) for the preparation of compounds of the formula I in which R₃ ishydrogen, the group Y₅ is eliminated from a compound of the formula IX##STR11## in which Y₅ is an amino-protective group, and R₂, R₄, X₁, X₂and X₃ have the indicated meanings, or from a salt thereof, or

f) for the preparation of compounds of the formula I in which X₃ isalkylene, compounds of the formulae X and XI ##STR12## in which Y₆ is agroup of the formula --N(R₃)--H, Y₇ is hydrogen, Y₈ and Y₉ together areoxo and Z₅ is an alkanylylidene radical corresponding to X₃, or Y₆ andY₇ together are oxo, Y₈ is a group of the formula --N(R₃)--H, Y₉ ishydrogen and Z₅ is a radical X₃, are condensed together under reducingconditions and, if required, a resulting compound is converted intoanother compound of the formula I, a mixture of isomers which can beobtained according to the process is fractionated into the components,and the isomer preferred in each case is separated off and/or a freecompound which can be obtained according to the process is convened intoa salt, or a salt which can be obtained according to the process isconverted into the corresponding free compound.

The carrying out of the reactions according to the process, and thepreparation of novel starting materials and intermediates takes place inanalogy to the way of reacting and forming known starting materials andintermediates respectively. The aids customary in each case are used forthis, even when not expressly mentioned hereinafter, such as catalysts,condensing and solvolysing agents and/or solvents or diluents, andreaction conditions such as temperature and pressure conditions, as wellas, where appropriate, protective gases.

Introduction of the radical R₁ according to process variant a) iscarried out in a conventional way, for example by reaction with an agentintroducing the radical R₁, such as an N-acylating agent of the formulaR₁ --Y_(a) (IIa1) in which R₁ is an optionally substituted aroyl,heteroaroyl, cycloalkylcarbonyl, aralkanoyl, heteroarylalkanoyl orarylcarbamoyl radical or the acyl radical of an optionallyN-alkanoylated α-amino acid and Y_(a) is optionally etherified hydroxy,such as hydroxy, lower alkoxycarbonyl or optionally substitutedphenyloxycarbonyl, or reactively esterified hydroxy, such as halogen,especially chlorine, or a radical of the formula --O--R₁, or with anaralkylating, aryloxyalkylating or heteroarylalkylating agent of theformula R₁ --Y_(b) (IIa2) in which R₁ is an optionally substitutedaralkyl, aryloxyalkyl, heteroaralkyl radical and Y_(b) is reactiveesterified hydroxyl, such as halogen, for example chlorine, bromine oriodine, or a sulfonyloxy group such as an alkane- or optionallysubstituted benzenesulfonyloxy group, for example methane-, ethane-,benzene-, p-toluene- or p-bromobemzenesulfonyloxy, or by reaction withunder reducing conditions with a compound of the formula R₁ ═O (IIa3) inwhich R₁ is an optionally substituted aralkyl, aryloxyalkyl,heteroaralkyl radical.

If necessary, the operation is carried out with thermal decomposition ofammonium salts formed as intermediates, or in the presence of acondensing agent such as a water-binding agent, or basic condensingagent, and in the presence of a solvent or diluent. Thus, reaction withacids of the formula IIa1 (Y═COOH) is preferably carried out in thepresence of a water-binding agent, such as ofN,N-dicyclohexylcarbodiimide, or with thermal decomposition of theammonium salt initially formed, while reaction with acid anhydrides ofthe formula IIa1 (Y═halogen or --O--(C═O)--R₁) and with compounds of theformula IIa2 is preferably carried out in the presence of a basiccondensing agent, such as of an alkali metal hydroxide or carbonate, orof a tertiary or sterically hindered secondary organic amine such as ofa tri-lower-alkylamine, for example of triethylamine ordiisopropylamine, or of an aromatic nitrogen base, for example ofpyridine.

Reaction of compounds of the formula IIa3 is carried out, for example,in the presence of hydrogen and of a hydrogenation catalyst such as of aplatinum or palladium catalyst or of, Raney nickel, or in the presenceof a di-light-metal hydride such as sodium borohydride or sodiumcyanoborohydride, preferably in a solvent which is inert under thereaction conditions, such as of a lower alkanol, such as methanol orethanol, or of a di-lower-alkyl or lower alkylene ether such as diethylether, dioxane or tetrahydrofuran.

The starting materials of the formula II can be prepared in aconventional way, for example by reacting compounds of the formulae##STR13## with one another, for example as described hereinafter forprocess variant b).

Reactive esterified hydroxyl in starting materials of the formula III orIV according to process variant b) means, for example, a halogen, suchas chlorine, bromine or iodine atom, or, if X₃ is different fromcarbonyl, denotes a sulfonyloxy group, for example methanesulfonyloxy orp-toluenesulfonyloxy, or, if X₃ represents carbonyl, denotes a group ofthe formula --O--(C═O)--R₄. Etherified hydroxyl means, for example,lower alkoxy such as methoxy or ethoxy, or optionally substitutedphenyloxy. Anhydridised hydroxyl is, for example, halogen, especiallychlorine, or a group of the formula --O--(C═O)--R₄.

Reaction of compounds of the formulae III and IV is carried out in aconventional way, for example with thermal decomposition of ammoniumsalts formed as intermediates, or in the presence of a condensing agentsuch as a water-binding agent, or basic condensing agent, and in thepresence of a solvent or diluent. Thus, reaction with acids of theformula IV or III (Y₂ or Y₁ ═OH) is preferably carried out in thepresence of a water-binding agent, such as ofN,N-dicyclohexylcarbodiimide, or with thermal decomposition of theammonium salt formed initially, while reaction with reactive esters ofthe formula IV or III (Y₂ or Y₁ =reactive esterified hydroxyl) or withacid anhydrides of the formula IV or III (Y₂ or Y₁ =anhydridisedhydroxyl) is preferably carried out in the presence of a basiccondensing agent, such as of an alkali metal hydroxide or carbonate, orof a tertiary or sterically hindered secondary organic amine, such as ofa tri-lower-alkylamine, for example of triethylamine ordiisopropylamine, or of an aromatic nitrogen base, for example ofpyridine.

The starting materials of the formula III can be prepared in aconventional way, for example by introducing the radical R₁ into acompound of the formula IIIa ##STR14## for example as described aboveunder process variant a).

Reductive replacement of the oxo or hydroxyl group in the α position tothe group --N(R₃)-- by hydrogen or the reduction of the double bond inthe radical of the formula --C(R_(a))═C(R_(b))-- according to processvariant c) is carried out, for example, by catalytic hydrogenation, thatis to say treatment with hydrogen in the presence of a hydrogenationcatalyst, such as of a metal or of a metal compound of a metal of groupVIIIb of the periodic table, such as platinum, plantinumoxide,palladium/carbon or of Raney nickel, or by reaction with aall-light-metal hydride such as an alkali metal borohydride, for examplewith sodium cyanoborohydride, of by treatment with formic acid.

Starting materials of the formula V or VI can, for example, bycondensation of compounds of the formulae Va and Vb ##STR15## in whichZ₁ ' is a direct linkage or a radical X₂ shortened by a C atom and Y₁ 'is hydrogen, lower alkyl or free, etherified or reactive esterifiedhydroxyl, and Z₂ has the indicated meaning, or of compounds of theformula VIa and VIb ##STR16## in which Z₁ has the indicated meaning, Z₂' is a direct linkage or a radical X₃ shortened by a C atom and Y₂ ' ishydrogen, lower alkyl or free, etherified or reactive esterifiedhydroxyl. If Y₁ ' in compounds of the formula Va or Y₂ ' in compounds ofthe formula VIb is hydrogen or lower alkyl there is formation of thecorresponding compounds of the formula V under mild reaction conditions,especially in a basic or neutral medium, and of the correspondingcompounds of the formula VI under drastic reaction conditions,especially in acid medium. In the last-mentioned case this entailsformation of the corresponding compounds of the formula V asintermediates, from which the corresponding compounds of the formula VIare then formed by elimination of water. Starting materials of theformulae V and VI can also be produced side by side. In a preferredembodiment of the invention, the intermediates of the formula V or VIare formed in situ and reduced without isolation to the correspondingcompounds of the formula I by carrying out the condensation of startingmaterials of the formulae Va and Vb or VIa and VIb in the presence ofone of the said reducing agent.

Optionally anhydridised or esterified carboxyl Y₃ or Y₄, respectively,in starting materials compounds of the formula VII or VIE for processvariant d) means, for example, halogenocarbonyl or, in the case of Y₄, agroup of the formula R₂ --C(═O)--O-- and a metallic radical Y₃ or Y₄,for example an alkali metal atom or a group of the formula --M^(II) /2or M^(II) --Hal in which M^(II) is a metal atom of group IIb of theperiodic table of the elements, such as Mg or Zn.

Reaction of compounds of the formulae VII and VIII is carried out in aconventional way, for example in an ether-like solvent such as analiphatic or cycloaliphatic ether, for example in diethyl ether,methoxybutane, dibutyl ether, tetrahydrofuran or dioxane

Starting materials of the formula VII in which Y₃ is formyl oroptionally anhydridised or esterified carboxyl are prepared, forexample, by condensing together compounds of the formulae VIIa and VIIIa##STR17## in which Y₁ is a group of the formula --N(R₃)--H and Y₂ ishydroxyl, are reactive esterified hydroxyl or, if X₃ is carbonyl,etherified or anhydridised hydroxyl, or Y₁ is hydroxyl, reactivelyesterified hydroxyl or, if X₂ is carbonyl, etherified or anhydridrisedhydroxyl and Y₂ is a group of the formula --N(R₃)--H, where R₂, R₃, R₄,X₁, X₂ and X₃ have the indicated meanings, or the salts thereof, forexample as indicated under process variant b).

Starting materials of the formulae VII and VIII in which Y₃ or Y₄ is ametallic radical are preferably prepared in situ by reacting a compoundof the formula VIIb ##STR18## in which Y'₃ is a halogen atom, especiallychlorine, bromine or iodine, with a metal of the formula M^(II), orstarting from compounds of the formula Y₄ '--R₂ (VIIIb) in which Y₄ ' ishydrogen or a halogen atom, especially chlorine, bromine or iodine,reacting a compound of the formula VIIIb in which Y₄ ' is hydrogen withan organometallic compound, for example a metal derivative of analiphatic hydrocarbon, for example with butyllithium, or reacting acompound of the formula VIIIb in which Y₄ ' is a halogen atom with ametal of the formula M^(II).

The amino-protective group Y₅ in starting materials of the formula IXaccording to process variant e) is, for example, an optionallyhalogenated lower alkanoyl group such as trifluoroacetyl, or an acylgroup derived from a monoester of carbonic acid, such as a loweralkoxycarbonyl or α-phenyl-lower-alkoxycarbonyl group, for exampleteritary butyloxycarbonyl or benzyloxycarbonyl, or a silyl group such astri-lower-alkylsilyl, for example trimethylsilyl. The elimination of theamino-protective group is carried out in a conventional way, for exampleby acid treatment, or starting from compounds IX in which Y₅ ishalogenated lower alkanoyl, such as trifluoroacetyl, by reductiveelimination, for example by treatment with a di-light-metal hydride suchas sodium borohydride, preferably in a lower alkanol such as methanol.

The starting materials of the formula IX can be prepared, for example,in analogy to process variant a) starting from corresponding compoundsof the formula IXa ##STR19##

Reaction of compounds of the formulae X and XI according to processvariant f) is carried out, for example, by elimination of water, forexample by azeotropic distillation, in particular with toluene, andsubsequent reduction with borane or a di-light-metal hydride such as analkali metal borohydride, for example with sodium boranate or sodiumcyanoborohydride.

Starting materials of the formula X, wherein R₁ denotes an acyl radicalas defined under formula I, X₁ is hydroxymethylene and Y₆ and Y₇together represent oxo, and their pharmaceutically acceptable salts,exhibit the same pharmacological properties and comparable activities asthe final products of formula I.

The inventions, therefore, relates also to 1-acylpiperidones of formulaX ##STR20## wherein R₁ is an optionally substituted aroyl, heteroaroyl,cycloalkylcarbonyl, aralkanoyl, heteroarylalkanoyl, aralkoxycarbonyl orarylcarbamoyl radical or the acyl radical of an α-amino acid which isoptionally N-substituted by lower alkanoyl or carbamoyl-lower-alkanoyl,R₂ is cycloalkyl or an optionally substituted aryl or heteroarylradical, X₁ denotes hydroxymethylene and Y₆ and Y₇ together representoxo, and to their salts, to a process for the preparation of thecompounds according to the invention, to pharmaceutical productscontaining these, and to their use as pharmaceutically activesubstances.

In these compounds, R₂ preferably has the meaning indicated for thecompounds of the formula I, above all the meaning indicated forespecially preferred compounds of formula I.

The invention most preferably relates to those compounds of formula X,wherein R₁ denotes benzoyl, benzoyl mono- or disubstituted by C₁ -C₄-alkyl, such as methyl, C₁ -C₄ -alkoxy, such as methoxy, halogen ofatomic number up to and including 35, such as chloro, and/ortrifluoromethyl or unsubstituted naphthoyl, R₂ represents phenyl orphenyl mono- or disubstituted by halogen of atomic number up to andincluding 35, such as chloro, and/or trifluoromethyl, X₁ denoteshydroxymethylene and Y₆ and Y₇ together represent oxo, and to theirsalts.

The invention specifically relates to the compounds or formula Xdescribed in the Examples herein and to their salts.

The compounds of formula X according to invention in which R₁ and R₂have the meanings indicated, X₁ denotes hydroxymethylene and Y₆ and Y₇together represent oxo, and their salts are prepared by methods knownper se. The process for their manufacture is characterised in that acompound of the formula Xa ##STR21## is condensated with an agentsuitable to introduce the group R₁ and, if required, a resultingcompound is converted into another compound of the formula I, a mixtureof isomers which can be obtained according to the process isfractionated into the components, and the isomer preferred in each caseis separated off and/or a free compound which can be obtained accordingto the process is convened into a salt, or a salt which can be obtainedaccording to the process is convened into the corresponding freecompound.

Agents suitable to introduce the group R₁ are, for example, compounds ofthe formula R₁ -Y₁₀ (Xb) in which Y₁₀ denotes reactive esterifiedhydroxy, such as halogen or a sulfonyloxy group, for example, benzene-,p-toluene- or methansulfonyloxy, or if R₁ denotes an aroyl-,heteroaroyl-, cycloalkylcarbonyl-, aralkanoyl-, heteroarylalkanoyl-,aralkoxycarbonyl- or arylcarbamoylrest or the acyl moiety of an α-aminoacid which may be N-substituted by lower alkanoyl or carbamoyl-loweralkanoyl, is etherified hydroxy, such as lower alkoxy or phenyloxy whichmay be substituted by halogen and/or nitro.

The condensation is performed in a manner, for example, in the presenceof a basic condensation adjuvan, such as in the presence of analkalimetall hydrogencarbonate, for example, of Sudiumhydrogencarbonate, preferably in a water-containing bi-phasic system,for example, in methylenechloride/water.

Compounds of formula Xa con, in turn, be obtained by reacting aN-protected piperidin-4-one ketal, such as1-(tert.-butyloxycarbonyl)piperindin-4-one ethyleneketal, with analdehyd of the formula R₂ --CH═O (Xc), for example in the presence of ahydorcarbon-metal, such as a hydorocarbon alkalimetal derivative,preferably of a lower-alkyl lithium compound, such as of sec.-butyllithium, preferably in an etheric solvent, such as diethyl ether, at-30° to -80° C., for example at -60° to -75° C.

Compounds of formula X, wherein Y₆ denotes a group of the formula--N(R₃)--H and Y₇ denotes hydrogen, are, for example, prepared bycondensing a compound of the formula R₂ --X₁ --Y (Xd) in which Y isreactive esterified hydroxyl, such as halogen, lower alkanesulfonyloxyor optionally substituted benzenesulfonyloxy, in the presence of analkali metal lower alkanolate such as sodium methanolate, in a loweralkanol such as methanol, or in the presence of sodamide in toluene witha lower alkyl but-2-ene-1, 1-dicarboxylate of the formula CH₂ ═CH--CH₂--CH(COOR)₂ (Xe; R=lower alkyl), hydrolysing and decarboxylating thereaction product of the formula Xf ##STR22## by treatment with an alkalimetal hydroxide, for example with potassium hydroxide in aqueousmethanol, amidating the resulting acid of the formula Xg ##STR23## forexample by treatment with a halogenating agent such as oxalyl chlorideor thionyl chloride followed by reaction with ammonia, and subsequentlydegrading to the corresponding amine of the formula Xh ##STR24##condensing the latter, after protection of the amino group, for exampleby acylation, with a lower alkoxymethyl halide of the formula RO--CH₂--Hal (Xf; R=lower alkyl; Hal=halogen), for example with chlorodimethylether in the presence of sodium hydroxide in dichloromethane/water,cyclocondensing the reaction product of the formula Xi ##STR25## by acidtreatment, for example treatment with a Lewis acid such as tintetrachloride, iron-III chloride, titanium tetrachloride, or protic acidsuch as sulfuric acid, chlorosulfonic acid, p-toluenesulfonic acid ortrifluoromethyl acetic acid or -methanesulfonic acid, in acetonitrileand, if required, acetic anhydride and another solvent such asdichloromethane, benzene or toluene, to the corresponding N-protectedcompound of the formula Xj ##STR26## eliminating the amino-protectivegroup, if required fractionating a resulting racemate into theenantiomers, introducing the group R₁ in a conventional way, forexample, as described hereinbefore for the manufacture of compounds offormula X, wherein X₁ denotes hydroxymethylene and Y₆ eliminating theamino-protecting group by acid treatment, for example with 6Nhydrochloric acid.

Compounds obtainable according to the process can be converted in aconventional way into other compounds of the formula I.

Thus, in compounds of the formula I in which X₁ is carbonyl can bereduced in a conventional manner to the corresponding compounds of theformula I in which X₁ is hydroxymethylene, for example as describedunder process variant c) or for the preparation of intermediates of theformulae V and VI. It is also possible in an analogous way for resultingcompounds of the formula I in which X₁ is hydroxymethylene or X₂ and/orX₃ is carbonyl can be reduced to the corresponding compounds of theformula I in which X₁, X₂ and/or X₃ is methylene.

The carbonyl group in resulting compounds of the formula I in which X₁is ketalised carbonyl can be liberated in a conventional way, forexample by acid treatment. Conversely, carbonyl X₁ can be ketalised byreaction with an appropriate alcohol such as a lower alkanol or a loweralkanediol.

It is furthermore possible in resulting compounds of the formula I inwhich R₃ is hydrogen to introduce a radical R₃ different from hydrogen,alkyl for example by conventional alkylation, carbamoyl for example bycondensation with isocyanic acid or a carbamoyl halide and alkanoyl oralkenoyl optionally substituted as indicated by conventional acylation.Conversely, in resulting compounds of the formula I in which R₃ isalkyl, especially methyl, the alkyl group can be eliminated by treatmentwith an ester, such as methylester, of haloformic acid.

Furthermore, esterified or amidated carboxyl as substituent of alkanoylor alkenoyl R₃ or of alkylene X₃ in resulting compounds of the formula Ican be hydrolysed to carboxyl or, conversely, free carboxyl can beesterified or amidated.

Resulting salts can be converted in a manner known per se into the freecompounds, for example by treatment with a base such as an alkali metalhydroxide, a metal carbonate or bicarbonate, or ammonia, or with anothersalt-forming base mentioned in the introduction, or with an acid such asa mineral acid, for example with hydrogen chloride, or with anothersalt-forming acid mentioned in the introduction.

Resulting salts can be convened in a manner known per se into othersalts, acid addition salts for example by treatment with a suitablemetal such as a sodium, barium or silver salt, of another acid in asuitable solvent in which an inorganic salt which forms is insoluble andthus separates out of the reaction mixture, and base salts by liberationof the free acid and renewed salt formation.

The compounds of the formula I, including their salts, can also beobtained in the form of hydrates or include the solvent used forcrystallisation.

As a consequence of the close relation between the novel compounds infree form and in the form of their salts, hereinbefore and hereinafterthe free compounds and their salts also mean, where appropriate for thesense and purpose, the corresponding salts and free compoundsrespectively.

Resulting mixtures of diastereomers and mixtures of racemates can alsobe fractionated on the basis of the physicochemical differences of thecomponents in a known manner into the pure diastereomers and racematesrespectively, for example by chromatography and/or fractionalcrystallisation.

Resulting racemates can furthermore be separated by known methods intothe optical antipodes, for example by recrystallisation from anoptically active solvent, with the aid of microorganisms or byconverting the resulting mixture of diastereomers or racemate with anoptically active auxiliary compound, for example appropriate for theacidic, basic or functionally modifiable groups contained in compoundsof the formula I with an optically active acid, base or an opticallyactive alcohol, into mixtures of diastereomeric salts or functionalderivatives such as esters, separation thereof into the diastereomersfrom which the enantiomer required in each case can be liberated in theway conventional in each case. Examples of bases, acids and alcoholssuitable therefore are optically active alkaloid bases such asstrychnine, cinchonine or brucine, or D- or L-(1-phenyl)ethylamine,3-pipecoline, ephedrine, amphetamine and similar bases obtainable bysynthesis, optically active carboxylic or sulfonic acids such as quinicacid or D- or L-tartaric acid, D- or L-di-o-toluyltartaric acid, D- orL-malic acid, D- or L-mandelic acid, or D- or L-camphorsulfonic acid, oroptically active alcohols such as borneol or L- or L-(1-phenyl)ethanol.

The invention also relates to those embodiments of the process whichstart from a compound obtainable as intermediate at any stage of theprocess and in which the missing steps are carried out or a startingmaterial is used in the form of a salt or, in particular, forms underthe reaction conditions.

The invention likewise relates to the novel starting materials whichhave been specifically developed for the preparation of the compoundsaccording to the invention, in particular the choice of startingmaterials leading to the compounds of the formula I which arecharacterised as preferred in the introduction, to the processes for thepreparation thereof and to the use thereof as intermediates.

The novel compounds of the formula I can be used, for example, in theform of pharmaceutical products which contain a therapeuticallyeffective amount of the active substance, where appropriate togetherwith inorganic or organic, solid or liquid, pharmaceutically utilisablevehicles which are suitable for enteral, for example oral, or parenteraladministration. Thus, tablets or gelatin capsules which contain theactive substance together with diluents, for example lactose, dextrose,sucrose, mannitol, sorbitol, cellulose and/or lubricants, for examplediatomaceous earth, talc, stearic acid or salts thereof, such asmagnesium or calcium stearate, and/or polyethylene glycol, are used.Tablets can likewise contain binders, for example magnesium aluminiumsilicate, starches such as maize, wheat, rice or arrowroot starch,gelatine, tragacanth, methylcellulose, sodium carboxymethylcelluloseand/or polyvinylpyrrolidone and, if desired, disintegrants, for examplestarches, agar, alginic acid or a salt thereof, for example sodiumalginate, and/or effervescent mixtures, or absorbents, colorants,flavourings and sweetners. It is furthermore possible to use the novelcompounds of the formula I in the form of products which can beadministered parenterally or of infusion solutions. Solutions of thistype are preferably isotonic aqueous solutions or suspensions, and thesecan, for example in the case of lyophilised products which contain theactive substance alone or together with a vehicle, for example mannitol,be prepared before use. The pharmaceutical products can be sterilisedand/or contain ancillary substances, for example preservatives,stabilisers, wetting agents and/or emulsifiers, solubilisers, salts toregulate the osmotic pressure and/or buffers. The present pharmaceuticalproducts, which can, if required, contain further pharmacologicallyactive substances, are prepared in a manner known per se, for example byconventional mixing, granulating, coating, dissolving or lyophilisingprocesses, and contain from about 0.1% to 100%, in particular from about1% to about 50%, lyophilisates up to about 100% of the active substance.

The invention likewise relates to the use of the compounds of theformula I, preferably in the form of pharmaceutical products. The dosagemay depend on a variety of factors such as mode of administration,species, age and/or individual condition. The doses to be administeredeach day are an oral administration of between about 0.25 and about 10mg/kg and, for warm-blooded animals with a body weight of about 70 kg,preferably between about 20 mg and about 500 mg.

The following examples serve to illustrate the invention; temperaturesare indicated in degrees celsius, pressures in mbar.

EXAMPLE 1

(2R,4S) and(2R,4R)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(2-phenethyl)-4-piperidinaminehydrochloride

1.26 g (17.1 mmol) of sodium cyanoborohydride (85%) are added inportions over the course of 10 minutes to a mixture of 3.65 g (11.4mmol) of (2R,4RS)-2-benzyl-1-(3,5-dimethylbenzoyl)-4-piperidinamine in30 ml of methanol, 935 mg (11.4 mmol) of sodium acetate, 0.65 ml (11.4mmol) of acetic acid and 1.44 g (12 mmol) of phenylacetaldehyde undernitrogen at 0°. The reaction mixture is then stirred at room temperaturefor 3 hours, a further 0.376 g (2.4 mmol) of phenylacetaldehyde isadded, and stirring is completed at 4° for 16 hours. The methanol isremoved in a rotary evaporator, and the reddish reaction mixture ispartitioned between ether and 1N sodium bicarbonate solution. Theorganic phases are washed with brine, dried over magnesium sulfate andevaporated to dryness. A mixture of the hydrochlorides of the titlecompounds of the formulae ##STR27## is obtained as a yellow oil. This ischromatogaphed on silica gel to separate the diastereomers using theeluent mixture methylene chloride/methanol/conc. ammonia(97.5:2.25:0.25), and the diasterereomers are obtained pure as freebases.

TLC: methylene chloride/methanol (98:2), Diastereomer A (2R,4R): R_(f)=0.16, melting point 248°-249° C., [α]_(D) =-56.9° (c=0.946,methanol),MS: M⁺ =426 (free base).

Diastereomer B (2R,4S): R_(f) =0.06, melting point 270° C.(decomposition), [α]_(D) =+30.6° (c=0.759, methanol), MS: M⁺ =426 (freebase).

The starting compounds for this are prepared as follows:

a) Ethyl (R)-3-benzylamino-4-phenylbutyrate

A total of 19.1 g of sodium cyanoborohydride (0.304 mol) is added inportions to a solution of 42.2 g (0.203 mmol) of ethyl(R)-3-amino-4-phenylbutyrate obtainable by esterification of the known(R)-3-amino-4-phenylbutyrate with ethanol, 11.6 ml (0.203 mol) ofglacial acetic acid, 33.3 g (0.406 mol) of sodium acetate and 20.9 ml((0.207 mol) of benzaldehyde in 400 ml of methanol at -5° to 5°. Afterthe addition is complete, reaction is allowed to go to completion atroom temperature for 1 hour. The yellow suspension is almost completelyconcentrated in a rotary evaporator, and the pasty residue ispartitioned between ethyl acetate and water which is adjusted to aboutpH 8 with ammonia solution. The organic phases are washed with water andbrine until neutral, dried over magnesium sulfate and evaporated todryness, resulting in a yellow oil. This is chromatographed on silicagel with methylene chloride/methanol 99:1, resulting in the titlecompound of the formula as a pale yellow oil. The oxolate is obtained byadding oxalic acid to an ethereal solution of the title compound.

Melting point 142°-143°. TLC: methylene chloride/methanol (95:5): R_(f)=0.63. MS: M⁺ -91=206 (60%), [α]_(D) =+3° (c=1, Ethanol) free base,[α]_(D) =-0.8° (c=1, CHCl₃) Oxalate, C₂₁ H₂₅ NO₆ (Oxalate): C calc.65.11%, found 65.12%.

    ______________________________________                                        H calc.  6.51%         found   6.46%                                          N calc.  3.62%         found   3.77%                                          ______________________________________                                    

b) Methyl(R)-N-benzyl-N-[(1-ethoxycarbonylmethyl-2-phenyl)ethyl]carbamoyl-acetate

A solution of 43.8 ml (0.408 mol) of methyl malonyl chloride in 480 mlof toluene is added dropwise over the course of 21/2 hours to asolution, cooled in an ice-water bath, of 115.8 g (0.389 mol) of ethyl(R)-3-benzylamino-4-phenylbutyrate, 56.8 ml (0.408 mol) of triethylamineand 366 mg of dimethylaminopyridine in 630 ml of toluene so that thetemperature remains within 0°-5°. The suspension is left to react tocompletion for 2 hours and then poured into 500 ml of ice-water. Theorganic phase is separated off, washed successively with 0.1Nhydrochloric acid solution, 1N sodium bicarbonate solution andice-water, and then dried over sodium sulfate and evaporated to dryness.The resulting yellow oil is chromatographed on silica gel with ethylacetate/hexane (1:2), resulting in the title compound.

TLC: ethyl acetate/hexane (1:2), R_(f) =0.25. MS: M⁺ =397 (3%), [α]_(D)=+19.5° (c=1.3, CHCl₃).

c) Methyl (6R)-1,6-dibenzyl-2,4-dioxo-3-piperidine carboxylate

15.2 g (0.135 mol) of potassium tertiary butanolate are added to asolution of 53.9 g (0.135 mol) of methyl(R)-N-benzyl-N-[(1-ethoxycarrbonylmethyl-2-phenyl)ethyl]carbamoyl-acetatein 520 ml of tert.-butanol at room temperature and left to react tocompletion for 1 hour. The pale yellow suspension is mixed at roomtemperature with 1 equivalent (8.1 g) of glacial acetic acid andconcentrated to a total volume of about 100 mi. The concentrate isdiluted with 300 ml of water and extracted 3 times with 300 ml of ethylacetate each time. The organic phases are subsequently washed with waterand brine, and the combined organic phases are dried over sodium sulfateand evaporated to dryness, resulting in the title compound of a clearyellow oil which is used further without further purification; TLC.ethyl acetate/methanol (1:1); R_(f) =0.3.

d) (6R)-1,6-Dibenzyl-2,4-piperidinedione

A solution of 106.1 g (0.301 mol) of methyl(6R)-1,6-dibenzyl-2,4-dioxo3-piperidine carboxylate in 298 ml of tolueneand 445 ml of 10% strength (vol/vol) acetic acid is heated at 80° for21/2 hours. The reaction mixture is cooled to room temperature,neutralised by adding 48 g of solid sodium carbonate while cooling inice-water, the phases are separated, and the aqueous phase is extractedonce more with 300 ml of ethyl acetate. The combined organic phases arewashed with water, then with brine dried over sodium sulfate andevaporated to dryness. The resulting oil is crystallised from ether,resulting in the title compound.

Melting point 97°-97.5°. TLC: ethyl acetate/hexane (2:1), R_(f) =0.31,[α]_(D) :+166.9° (c=1, CHCl₃), MS: M⁺ =293 (2.4%).

e) (2R,4RS)-1,2-Dibenzyl-4-piperidinamine

(Variant e1)

e1a) 6R)-1,6-Dibenzyl-4-(methoxyimino)-2-piperidone

A solution of 10 g (0.034 mol) of (6R)-1,6-dibenzyl-2,4-piperidinedionein 68 ml of pyridine is mixed with 3.09 g (0.037 mol) of methoxyaminehydrochloride and heated at 85° for 1 h. The clear yellow solution ispoured into ice-cold 1N hydrochloric acid solution (pH about 3) andextracted with toluene. The organic extracts are washed with 1Nhydrochloric acid solution, then with 1N sodium carbonate solution andwith brine. This is followed by drying over sodium sulfate andevaporating to dryness, resulting in the title compound in the form ofwaxy crystals.

Melting point 63°-77°. TLC: ethyl acetate/hexane (1: 1), R_(f) =0.52,MS: M⁺ : 322 (1.4%).

On the basis of the ¹ H NMR (CDCl₃) a syn/anti mixture in the ratio ofabout 7:3 is present, methoxy signals of the oxime ether at 3.92 and3.88 ppm.

e1b) (2R,4RS)-1,2-Dibenzyl-4-piperidinamine

A solution of 9.19 g (0.0285 mol) of(6R)-1,6-dibenzyl-4-(methoxyimino)-2-piperidone in 90 ml oftetrahydrofuran is heated to reflux under argon in a distillationapparatus with fitted Vigreux column and condenser through which waterat 40° flows. To this solution are added dropwise over the course of 20minutes 6.1 ml (0.0643 mol) of borane/dimethyl sulfide complex followedby a second addition of 9 ml (0.0949 mol) of borane/dimethyl sulfidecomplex over the course of 4 hours. During the addition of theborane/dimethyl sulfide complex, the liberated dimethyl sulfide escapesthrough the distillation apparatus.

After the addition is complete, the reaction mixture is cooled to 0°-4°in an ice-water bath, and excess borane is hydrolysed by slow additionof a total of 20 ml of methanol. After the vigorous, exothermichydrolysis has subsided, the solvent is removed directly from theapparatus under water-pump vacuum. The residue is then boiled for 2hours after addition of 90 ml of 5N hydrochloric acid solution. Thesolution is cooled to room temperature and diluted with 200 ml of waterand extracted with ether to remove the acid and neutral portion, thenthe aqueous phase is cooled in an ice-water bath, adjusted to about pH 9with 5N sodium hydroxide solution, and the base portion is extractedwith ether/tetrahydrofuran (2:1). The organic extracts are dried overmagnesium sulfate and evaporated to dryness, resulting in the crude basein the form of a yellowish oil. This is employed directly in the nextstage; TLC: methylene chloride/methanol/conc. ammonia (90: 10:0.4),R_(f) =0.3.

Amorphous dihydrochloride of the title compound is precipitated bydissolving in methanolic hydrochloric acid solution and adding ether;melting point 150°-182°.

Variant e2)

e2a) (6R)-1,6-Dibenzyl-2,4-piperidinedione 4-ethylene ketal

A solution of 30 g (0.102 mol) of (6R)-1,6-dibenzyl-2,4-piperidinedione,50 ml of ethylene glycol and 1.8 g of p-toluenesulfonic acid monohydratein 800 ml of toluene is heated with a water separator for 3 h. Thesolution is cooled to room temperature and washed with 100 ml of 1Nsodium bicarbonate solution and brine, and the organic phase is driedover magnesium sulfate and evaporated to dryness, resulting in the crudeketal as oil. This is chromatographed on silica gel with ethyl acetate,and the oil resulting from the chromatography is crystallised fromether, resulting in the title compound in the form of white crystals.

Melting point 91°-93°. TLC: ethyl acetate/hexane (3:1), R_(f) =0.53, MS:M⁺ : 337.

e2b) (2R)-1,2-Dibenzyl-4-piperidone ethylene ketal

7.6 ml (0.0756 mol) of borane/dimethyl sulfide complex are added overthe course of 10 minutes to a solution of 10.2 g (0.0302 mol) of(6R)-1,6-dibenzyl-2,4-piperidinedione 4-ethylene ketal in 100 ml oftetrahydrofuran under argon, and the mixture is heated to reflux for 1h. The solution is cooled to room temperature and then 40 ml of 2Nsodium hydroxide solution are added, and heating to reflux is resumedfor 2 h, and subsequently the tetrahydrofuran is removed in a rotaryevaporator and the reaction mixture is extracted with ether the organicextracts are washed with sodium bicarbonate, dried over magnesiumsulfate and evaporated to dryness, resulting in the title compound; TLC:ethyl acetate/hexane (2:1), R_(f) =0.81; MS: M⁺ : 323.

e2c) (2R)-1,2-Dibenzyl-4-piperidone

A solution of 85.7 g (0.261 mol) of (2R)-1,2-dibenzyl-4-piperidoneethylene ketal in 170 ml of dioxane and 1000 ml of 2.25M hydrochloricacid solution are heated at 70° for 29 hours. The dioxane is thenremoved in vacuo, the aqueous phase is adjusted to about pH 8 with 30%strength sodium hydroxide solution while cooling in ice-water and isextracted with ether the ether extracts are washed with 1N sodiumbicarbonate solution, dried over sodium sulfate and evaporated todryness, resulting in the title compound as a reddish oil which, becauseof its instability, is further processed without further purification;TLC: ethyl acetate/hexane (1:1); R_(f) =0.71; FD-MS: M⁺ : 279.

e2d) (2R)-1,2-Dibenzyl-4-(methoxyimino)piperidine

3 g (0.01071 mol) of (2R)-1,2-dibenzyl-4-piperidone, 4.4 g (0.0537 mol)of sodium acetate and 942 mg (0.0113 mol) of methoxyamine hydrochlorideare dissolved in 30 ml of ethanol, and the suspension is heated at 60°for 30 minutes. The ethanol is then removed in vacuo, and the residue ispartitioned between water and ethyl acetate, and the organic extractsare dried over sodium sulfate and evaporated to dryness, resulting inthe crude product. This is chromatographed on silica gel with ethylacetate/hexane (3:1), resulting in the title compound in the form of anoil.

TLC: ethyl acetate/hexane (1:1), R_(f) =0.84, Rf₂ =0.76 (syn/anti oximeethers), MS: M⁺ : 308 (1%), M⁺ -91:217 (90%). ¹ H-NMR-spectrum (CD₃ OD),δ(ppm)=3.85 (s, ═N--OCH₃), 3.825 (s): approx. 1:1.

e2e) (2R,4RS)-12-Dibenzyl-4-piperidinamine

180 ml of gaseous ammonia which has been dried over potassium hydroxideare condensed into a solution of 5.43 g (17.6 mmol) of(2R)-1,2-dibenzyl-4(methoxyimino)piperidine in 60 ml of tetrahydrofuranat -78°. To this solution are added at -70° 3.7 g (69 mmol) of ammoniumchloride and, in portions, 1.6 g (70.4 mmol) of sodium metal. After onehour, a further 3.7 g of ammonium chloride and 0.6 g of sodium metal areadded to the resulting suspension, which is then stirred at -70° for 2hours. The cooling bath is then removed and the gaseous ammonia isallowed to evaporate. The residue is partitioned between 1N sodiumhydroxide solution and ether, the organic phase is separated off, theaqueous phase is back-extracted, the organic phases are washed withbrine, and the combined organic phases are dried over sodium sulfate andevaporated to dryness, resulting in the title compound in the form of ayellow oil; TLC: methylene chloride/methanol/cone. ammonia (90:9:1),R_(f) =0.33); MS: M⁺ =280.

f) (2R,4RS)-N-(1,2-Dibenzyl-4-piperidyl)trifiuoroacetamidetrifluoroacetate

5.1 ml (36.8 mmol) of trifluoroacetic anhydride are added to a solutionof 6.88 g (24.5 mmol) of (2R,4RS)-1,2-dibenzyl-4-piperidinamine in 20 mlof methylene chloride in an ice-water bath, and stirring is thencompleted at room temperature for 1 hour. The reaction mixture isevaporated to dryness, resulting in the title compound as pale yellowfoam; TLC: methylene chloride/methanol/conc. ammonia (190:9:1), R_(f)=0.41 (cis) and 0.57 (trans) diastereomer; MS: M⁺ -91 (benzyl)=285(14%).

g) (2R,4RS)-N-(2-Benzyl-4-piperidyl)trifiuoroacetamide trifluoroacetate

3.0 g of 10% palladium catalyst on carbon are added to a solution of19.3 g (39.4 mmol) of(2R,4RS)-N-(1,2-dibenzyl-4piperidyl)trifluoroacetamide trifluoroacetatein 160 ml of dioxane under nitrogen, and hydrogenation is carried outunder atmospheric pressure at room temperature. The reaction mixture isfreed of catalyst over Celite® and the residue is washed with dioxane.The filtrate is evaporated to dryness and dried under high vacuum,resulting in the title compound which is used further without furtherpurification; TLC: methylene chloride/methanol/conc. ammonia (90:9:1)R_(f) =0.24 and 0.3 (two poorly separated diastereomers).

h)(2R,4RS)-N-[2-Benzyl-1-(3,5-dimethylbenzoyl)-4-piperidyl]trifluoroacetamid

710 mg of solid sodium bicarbonate and 712 mg of 3,5-dimethylbenzoylchloride are added to a stirred mixture of 1.39 g (3.44 mmol) of(2R,4RS)-N-(2-benzyl-4-piperidyl)trifiuoroacetamide trifluoroacetate and10 ml of toluene/water (1:1) cooled in ice-water. The reaction mixtureis then allowed to warm to room temperature, subsequently stirred for 2hours and partitioned between toluene and 1N sodium bicarbonatesolution. The organic phases are washed with water, dried over magnesiumsulfate and evaporated to dryness. The colourless oil is chromatographedon silica gel with ethyl acetate/hexane 1:2, resulting in the titlecompound. This is used further without further purification.

TLC: methylene chloride/methanol/conc. ammonia (190:9:1) R_(f) =0.5, (noseparation of the two diastereomers under these conditions), MS: M⁺ =418(3%), M⁺ -91 (43%).

i) (2R,4RS)-2-Benzyl-1-(3,5-dimethylbenzoyl)-4-piperidinamine

4.1 ml of 5N sodium hydroxide solution are added to a solution of 4.73 g(10.4 mmol) of(2R,4RS)-N-[2-benzyl-1-(3,5-dimethylbenzoyl)-4-piperidyl]trifluoroacetamidein 50 ml of tetrahydrofuran/methanol 1:1 at room temperature undernitrogen, and the mixture is heated to reflux for 3 hours. After thereaction is complete, the reaction mixture is cooled in ice-water,adjusted to about pH 1 with 1N hydrochloric acid solution, and theorganic solvent is removed in a rotary evaporator. The remaining acidicaqueous phase is extracted first with ether to remove acidic and neutralportions, and is then adjusted to about pH 10 by adding 10N sodiumhydroxide solution while cooling in ice-water and is extracted withether. The organic phases are washed with brine, dried over sodiumsulfate and evaporated to dryness, resulting in the free base asbrownish oil, which is used further without purification; TLC: methylenechloride/methanol/cone. ammonia (90:9:1) R_(f) =0.29; MS: M⁺ =322(0.03%), M⁺ 91=231 (62%).

(2S,4RS)2-Benzyl-1-(3,5-dimethylbenzoyl)-4-piperidinamine is obtainedanalogously thereto starting from L-phenylalaninol in accordance withthe above reaction sequence.

EXAMPLE 2

(2R*,4S*)-2-Benzyl-1-(2-naphthoyl)-N-(4-quinolylmethyl)-4-piperidinamine

28 mg (0.73 mmol) of sodium borohydride are added in three portions overthe course of 20 minutes to a solution of 106 mg (0.182 mmol) of(2R*,4S*)-2-benzyl-1-(2-naphthoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinaminein 1.5 ml of methanol at 0°, and the mixture is subsequently stirred at0° for 3 hours. 0.06 ml (0.81 mmol) of acetone is then added to thereaction mixture, and the stirring is completed for 10 minutes. Themethanol is removed in a rotary evaporator, and the solid white residueis partitioned between ethyl acetate and water. The organic phases arewashed with brine, dried over magnesium sulfate and evaporated todryness. The resulting white foam is chromatographed with methylenechloride/methanol/conc. ammonia (1500:50:1) on silica gel. The titlecompound of the formula ##STR28## as white foam is obtained as whitefoam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) R_(f)=0.34, FD-MS: M⁺ =485.

The starting compound for this is prepared as follows:

a) 2-Benzyl-N-benzyloxycarbonyl-2,3-dihydro-4-(1H)-pyridone

165 ml (1.16 mol) of benzyl chloroformate are added dropwise over thecourse of 20 minutes to a solution of 104 g (0.95 mol) of4-methoxypyridine in 1 l of anhydrous tetrahydrofuran at -70° underargon. The thick beige suspension is then diluted with 200 ml ofanhydrous tetrahydrofuran. The Grignard reagent prepared from 460 ml(1.46 mol) of a 3 molar solution of benzyl chloride in anhydrous etherand 35.5 g (1.46 mol) of magnesium turnings in 160 ml of anhydrous etheris then added dropwise to the reaction mixture over the course of 75minutes, maintaining the temperature at -70°. After a further 10minutes, it is allowed to warm to room temperature. It is diluted with500 ml of ether, 900 ml of 4N hydrochloric acid are added dropwise, andthe phases are separated. The organic phases are washed with water andbrine, dried over magnesium sulfate and evaporated to dryness. Theresidue is chromatographed on silica gel with hexane/ethyl acetate(3:1). The title compound is obtained as a colourless viscous oil. TLC:hexane/ethyl acetate (1:3) R_(f) =0.7, IR: 1725, 1665, 1602 cm⁻¹.

b) (2R*,4R*)-2-Benzyl-4-hydroxypiperidine

150 g (0.467 mol) of2-benzyl-N-benzyloxycarbonyl-2,3-dihydro-4-(1H)-pyridone in 1.5 l ofmethanol are hydrogenated with 7.5 g of Pd/C (10%) as catalyst, then 50g of Raney nickel and a further 200 ml of methanol are added, andhydrogenation is left to go to completion. Filtration is followed byevaporation in a rotary evaporator, and the brownish oil ischromatographed on silica gel with methylene chloride/methanol/conc.ammonia (60:10:1). The title compound is obtained as a semi-crystallinemass which is used further without additional purification.Crystallisation of a sample from ether/hexane yielded white crystals ofmelting point 111°-112°. TLC: methylene chloride/methanol/conc. ammonia(40:10:1) R_(f) =0.55, FD-MS: M⁺ =191.

c) (2R*,4R*)-2-Benzyl-1-t-butyloxycarbonyl-4-hydroxy-piperidine

A solution of 28 g (146 mmol) of (2R*,4R*)-2-benzyl-2-hydroxypiperidineand 35.1 g (161 mmol) of di-tert-butyl dicarbonate in 500 ml ofchloroform is stirred at 50° for 20 hours. It is then concentrated in arotary evaporator, and the yellow oil is chromatographed on silica gelwith methylene chloride/methanol/conc. ammonia (2000:50:1). The titlecompound is obtained as yellow oil. TLC: methylenechloride/methanol/conc. ammonia (2000:50:1) R_(f) =0.43, FD-MS: M⁺ =291.

d)(2R*,4R*)-2-Benzyl-1-t-butyloxycarbonyl-4-methanesulfonyloxy-hydroxypiperidine

33.3 ml (428 mmol) of methanesulfonyl chloride are added dropwise to asolution of 62.4 g (214 mmol) of(2R*,4R*)-2-benzyl-1-t-butyloxycarbonyl-4-hydroxypiperidine in 75 ml ofpyridine while cooling in ice. After 30 minutes at 0°, stirring of thesuspension is completed at room temperature for 3 hours. Afterconcentration in a rotary evaporator, the reaction mixture is taken upin ethyl acetate, washed with water and brine, dried over magnesiumsulfate and evaporated in a rotary evaporator. The title compoundcrystallises from ether as white crystals; melting point 110°-115°; TLC:toluene/ethyl acetate (4:1) R_(f) =0.42, FD-MS: M⁺ =369.

e) (2R*,4S*)-2-Benzyl-1-t-butyloxycarbonyl-4-piperidine azide

A mixture of 98.9 g (267 mmol) of(2R*,4R*)-2-benzyl-1-t-butyloxycarbonyl-4-methansulfonyloxy-hydroxypiperidine,14.4 g (294 mmol) of lithium azide and 500 ml of N,N-dimethylformamideis stirred at 80° under argon for 3 hours. The reaction mixture isdiluted with ethyl acetate and washed with water and brine, dried overmagnesium sulfate and evaporated to dryness. The brownish oil ischromatographed on silica gel with toluene/ethyl acetate (9:1) aseluent. The title compound is obtained mixed with2-benzyl-N-t-butyloxycarbonyl-1,2,5,6-tetrahydropyridine (ratio=4.2:1 byweight according to ¹ HNMR) which is not fractionated further. TLC:toluene/ethyl acetate (9:1) R_(f) =0.59, FD-MS: M⁺ =316, IR: 2100, 1685cm⁻¹.

f) (2R*,4S*)-2-Benzyl-1-t-butyloxycarbonyl-4-piperidinamine

A mixture of 4.16 g (13.1 mmol) of(2R*,4S*)-2-benzyl-1-t-butyloxycarbonyl-4-piperidine azide and 0.99 g(3.62 mmol) of 2-benzyl-N-t-butyloxycarbonyl-1,2,5,6-tetrahydropyridine(calculated on the basis of the ¹ H-NMR spectrum) in 100 ml of methanolis hydrogenated with hydrogen and 1 g of 10% Pd/C. After the hydrogenuptake is complete, the mixture is filtered and evaporated in a rotaryevaporator. The brown oil is chromatographed on silica gel withmethylene chloride/methanol/conc. ammonia (350:50:1). The title compoundis obtained as a yellow oil. TLC: methylene chloride/methanol/conc.ammonia (350:50:1) R_(f) =0.4, FD-MS: M⁺ =290.

g)(2R*,4S*)-2-Benzyl-1-t-butyloxycarbonyl-N-(4-quinolylmethyl)-4-piperidinamine

A mixture of 5 g (17.2 mmol) of(2R*,4S*)-2-benzyl-1-t-butyloxycarbonyl-4-piperidinamine and 2.7 g (17.2mmol) of quinoline-4-carboxaldehyde in 50 ml of toluene is stirred atroom temperature and, after 2 hours, 2.8 g (23.3 mmol) of anhydrousmagnesium sulfate are added. After a further 16 hours, the mixture isfiltered and the filtrate is concentrated. The brown oil is dissolved in50 ml of methanol, and 0.69 g (18.3 mmol) of sodium borohydride is addedin 4 portions. After stirring at room temperature for 3 hours, thereaction mixture is concentrated, taken in ethyl acetate and washed withwater and brine. The organic phases are dried over magnesium sulfate andevaporated to dryness. The brown oil is chromatographed on silica gelwith methylene chloride/methanol/conc. ammonia 850:50:1). The titlecompound is obtained as yellow oil. TLC: methylenechloride/methanol/conc. ammonia (700:50:1) R_(f) =0.38, FD-MS: M⁺ =431.

h)(2R*,4S*)-2-Benzyl-1-t-butyloxycarbonyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

2.2 ml (15.8 mmol) of trifluoroacetic anhydride are added to a solutionof 6.2 g (14.4 mmol) of(2R*,4S*)-2-benzyl-1-t-butyloxycarbonyl-N-(4-quinolylmethyl)-4-piperidinamineand 2.6 ml (18.7 mmol) of triethylamine in 60 ml of methylene chlorideat 0° under argon, and the reaction mixture is stirred at 0° for 3hours. It is diluted with methylene chloride and washed with water. Theorganic phases are dried over magnesium sulfate and evaporated todryness. The title compound is obtained as TLC-pure product as yellowoil. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) R_(f)=0.62, DCI-MS: (M+H)⁺ =528.

i)(2R*,4S*)-2-Benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

250 ml of 6N hydrogen chloride in dioxane is added dropwise over thecourse of 3 minutes to 7.73 g (14.7 mmol) of(2R*,4S*)-2-benzyl-1-t-butyloxycarbonyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinaminewhile cooling in ice, and the mixture is subsequently stirred at roomtemperature for 1 hour. The reaction mixture is concentrated in a rotaryevaporator, basified with 1N sodium bicarbonate solution and extractedwith methylene chloride. The organic phases are dried over magnesiumsulfate and evaporated to dryness. The brownish oil (7.14 g) ischromatographed on silica gel with methylene chloride/methanol/conc.ammonia (700:50:1). The title compound is obtained as yellow oil. TLC:methylene chloride/methanol/conc. ammonia (700:50:1) R_(f) =0.42,DCI-MS: (M+H)⁺ =428, IR: 1690 cm⁻¹.

j)(2R*,4S*)-2-Benzyl-1-(2-naphthoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

A solution of 58 μl (0.795 mmol) of thionyl chloride in 0.2 ml oftoluene is added dropwise to a solution of 97 mg (0.56 mmol) of2-naphthoic acid in 1 ml of toluene over the course of 10 minutes at 50°under argon, and the reaction mixture is stirred at 80° for 2 hours. Itis then concentrated in a rotary evaporator, and 1 ml of toluene isadded, and evaporation is repeated, twice each. The brown oil isdissolved in 1 ml of methylene chloride and added under argon to asolution of 200 mg (0.468 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineat 0° and stirred at 0° for 2 hours. Water is subsequently added to thereaction mixture, and extraction with methylene chloride is carried out.The organic phases are washed with brine, dried over magnesium sulfateand evaporated to dryness. The yellow oil is chromatographed on silicagel with methylene chloride/methanol/conc. ammonia (1000:50:1). Thetitle compound is obtained as yellow oil. TLC: methylenechloride/methanol/conc. ammonia (2000:50:1) R_(f) =0.36, FD-MS: M⁺ =581.

EXAMPLE 3

(2R*,4S*)-2-benzyl-1-(3-trifluoromethylbenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine

0.184 g (0.307 mmol) of(2R*,4S*)-2-benzyl-1-(3-trifluoromethylbenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineis reacted with 0.046 g (1.23 mmol) of sodium borohydride in analogy toExample 2. The title compound of the formula ##STR29## is obtained asyellow oil. TLC: methylene chloride/methanol/conc. ammonia (700:50:1)R_(f) =0.28, FD-MS: M⁺ =503.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(3-trifluoromethylbenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

106 mg (0.56 mmol) of 3-trifluoromethylbenzoic acid are reacted inanalogy to Example 2j first with 58 μl (0.795 mmol) of thionyl chlorideand subsequently with 200 mg (0.468 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineto give the product. TLC: methylene chloride/methanol/conc. ammonia(700:50:1) R_(f) =0.56, FD-MS: M⁺ =599.

EXAMPLE 4

(2R*,4S*)-2-benzyl-1-(3,5-bis-(trifluoromethyl)-benzoyl)-N-(4-quinolylmethyl)-4-piperidinamine

0.271 g (0.406 mmol) of(2R*,4S*)-2-benzyl-1-(3,5-bis-(trifluoromethyl)-benzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineis reacted with 0.061 g (1.23 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR30## is obtained as white foam. TLC:methylene chloride/methanol/conc. ammonia (1000:50:1) R_(f) =0.21,FD-MS: M⁺ =571.

The starting compound for this is prepared as follows:(2R*,4S*)-2-Benzyl-1-(3,5-bis-(trifluoromethyl)-benzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

143 mg (561 mmol) of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride and144 μl (1.03 mmol) of triethylamine are added to a solution of 200 mg(467 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineand 113 mg (561 mmol) of 3,5-bis-(trifluoromethyl)-benzoic acid in 3 mlof methylene chloride, and the reaction mixture is left to stir at roomtemperature for 16 hours. It is then diluted with methylene chloride,and the organic phase is washed once each with 10% strength citric acid,1N sodium bicarbonate solution and with brine, dried over magnesiumsulfate and evaporated to dryness. The yellowish foam is chromatographedon silica gel with methylene chloride/methanol/conc. ammonia(1000:50:1). The title compound is obtained as yellow oil. TLC:methylene chloride/methanol/conc. ammonia (1000:50:1) R_(f) =0.34,FD-MS: M⁺ =667.

EXAMPLE 5

(2R*,4S*)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine

250 mg (0.423 mmol) of(2R*,4S*)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted with 64 mg (1.69 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR31## is obtained as white foam. TLC:methylene chloride/methanol/conc. ammonia (1000:50:1) R_(f) =0.23,DCI-MS: (M+H)⁺ =496.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(3,5-dimethoxybenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

200 mg (0.467 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted with 102 mg (0.561 mmol) of 3,5-dimethoxybenzoic acid, 143mg (0.561 mmol) of bis(2-oxo-3-oxazolidinyl)phosphinic chloride and 144μl (1.03 mmol) of triethylamine in analogy to Example 4. The titlecompound is obtained as white foam. TLC: methylenechloride/methanol/conc. ammonia (1000:50:1) R_(f) =0.31, FD-MS: M⁺ =591.

EXAMPLE 6

(2R*,4S*)-2-benzyl-1-(1-naphthoyl)-N-(4-quinotylmethyl)-4-piperidinamine

200 mg (0.344 mmol) of(2R*,4S*)-2-benzyl-1-(1-naphthoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted with 52 mg (1.37 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR32## is obtained as white foam. TLC:methylene chloride/methanol/conc. ammonia (1000:50:1) R_(f) =0.35,FD-MS: M⁺ =485.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(1-naphthoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

92 μl (0.655 mmol) of 1-chloro-N,N,2-trimethyl-1-propen-1-amine areadded to a solution of 96 mg (0.561 mmol) of 1-naphthoic acid in 2 ml ofdry, methylene chloride at 0°, and the mixture is stirred at 0° for 1hour and at room temperature for 1 hour. Subsequently a solution of 200mg (0.468 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineand 130 μl (0.936 mmol) of triethylamine in 3 ml of methylene chlorideis added dropwise over the course of 10 minutes to this yellow solutionat room temperature. After stirring at room temperature for 3 hours,water is added, the organic phase is separated off and washed twice morewith water. The organic phases are dried over magnesium sulfate andevaporated to dryness. The yellow oil is chromatographed on silica gelwith methylene chloride/methanol/conc. ammonia (800:50:1). The titlecompound is obtained as yellow oil. TLC: methylenechloride/methanol/conc. ammonia (700:50:1) R_(f) =0.49, FD-MS: M⁺ =581.

EXAMPLE 7

(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine

1.21 g (2.01 mmol) of(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted with 0.305 mg (8.06 mmol) of sodium borohydride in analogyto Example 2. The title compound ##STR33## is obtained as white foam;TLC: methylene chloride/methanol/conc. ammonia (700:50:1) R_(f) =0.37;FD-MS: M⁺ =503.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

1.11 g (5.85 mmol) of 3,5-dichlorobenzoic acid are reacted in analogy toExample 2j first with 0.63 ml (8.77 mmol) of thionyl chloride andsubsequently with 1 g (2.34 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineto give the product. TLC: methylene chloride/methanol/conc. ammonia(700:50:1) R_(f) =0.65, FD-MS: M⁺ =599.

EXAMPLE 8

(2R*,4S*)-2-benzyl-1-(2-quinolinylcarbonyl)-N-(4-quinolylmethyl)-4-piperidinamine

155 mg (0.266 mmol) of(2R*,4S*)-2-benzyl-1-(2-quinolinylcarbonyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted with 40 mg (1.06 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR34## is obtained as white foam. TLC:methylene chloride/methanol/conc. ammonia (700:50:1) R_(f) =0.42, D-MS:M⁺ =486.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(2-quinolinylcarbonyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine97 mg (0.56 mmol) of quinoline-2-carboxylic acid are reacted in analogyto Example 2j first with 58 μl (0.795 mmol) of thionyl chloride andsubsequently with 200 mg (0.468 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineto give the product. TLC: methylene chloride/methanol/conc. ammonia(700:50:1) R_(f) =0.45, FD-MS: M⁺ =582.

EXAMPLE 9

(2R*,4S*)-2-benzyl-1-(4-chlorophenylacetyl)-N-(4-quinolylmethyl)-4-piperidinamine

256 mg (0.441 mmol) of(2R*,4S*)-2-benzyl-1-(4-chlorophenylacetyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted with 66 mg (1.76 mmol) of sodium borohydride in analogoy toExample 2. The title compound ##STR35## is obtained as white foam. TLC:methylene chloride/methanol/conc. ammonia (700:50:1) R_(f) =0.48, FD-MS:M⁺ =484.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(4-chlorophenylacetyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

96 mg (0.56 mmol) of 4-chlorophenylacetic acid are reacted in analogy toExample 2j first with 58 μl (0.795 mmol) of thionyl chloride andsubsequently with 200 mg (0.468 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineto give the product. TLC: methylene chloride/methanol/conc. ammonia(700:50:1) R_(f) =0.39, FD-MS: M⁺ =580.

EXAMPLE 10

(2R*,4S*)-2-benzyl-1-(benzyloxycarbonyl)-N-(4-quinolylmethyl)-4-piperidinamine

80 mg (0.142 mmol) of(2R*,4S*)-2-benzyl-1-(benzyloxycarbonyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted with 22 mg (0.57 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR36## is obtained as colourless oil.TLC: methylene chloride/methanol/conc. ammonia (700:50:1) R_(f) =0.43,FD-MS: M⁺ =465.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(benzyloxycarbonyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

67 μl (0.468 mmol) of benzyl chloroformate and 72 μl (0.515 mol) oftriethylamine are added to a solution of 200 mg (0.468 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinaminein 4 ml methylene chloride at 0°, and the mixture is left to stir atthis temperature for 16 hours. Then a further 34 μl (0.234 mmol) ofbenzyl chloroformate and 36 μl (0.257 mmol) of triethylamine are addedand stirred at room temperature for 3 hours. This is followed bydilution with methylene chloride, and the organic phase is washed withbrine, dried over magnesium sulfate and evaporated to dryness. The oilis chromatographed on silica gel with methylene chloride/methanol/conc.ammonia (1000:50:1). The title compound is obtained as oil. TLC:methylene chloride/methanol/conc. ammonia (700:50:1) R_(f) =0.61, FD-MS:M⁺ =561.

EXAMPLE 11

(2R*,4S*)-2-benzyl-1-(2-phenylethyl)-N-(4-quinolylmethyl)-4-piperidinamine

215 mg (0.494 mmol) of(2R*,4S*)-2-benzyl-1-(2-phenylethyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted with 77 mg (1.97 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR37## is obtained as oil. TLC:methylene chloride/methanol/conc. ammonia (700:50:1) R_(f) =0.34, FD-MS:M⁺ =435.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(2-phenylethyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

209 μl (0.936 mmol) of phenylacetaldehyde are added dropwise over thecourse of 10 minutes to a solution of 100 mg (0.233 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine,58 mg (0.702 mmol) of sodium acetate, 44 mg (0.702 mmol) of sodiumcyanoborohydride and 67 μl (1.17 mmol) of acetic acid in 2 ml of ethanolat room temperature. The reaction mixture is left to stir at roomtemperature for 16 hours. The residue after evaporation in a rotaryevaporator is taken up in ethyl acetate, and the organic phase is washedwith water and with brine, dried over magnesium sulfate and evaporatedto dryness. The yellow oil is chromatographed on silica gel withmethylene chloride/methanol/conc. ammonia (2000:50:1). The titlecompound is obtained as oil. TLC: methylene chloride/methanol/conc.ammonia (2000:50:1) R_(f) =0.33, FD-MS: M⁺ =531.

EXAMPLE 12

(2R*,4S*)-2-benzyl-1-(2-naphthylacetyl)-N-(4-quinolylmethyl)-4-piperidinamine

160 mg (0.269 mmol) of(2R*,4S*)-2-benzyl-1-(2-naphthylacetyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted with 42 mg (1.13 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR38## is obtained as colourless oil.TLC: methylene chloride/methanol/conc. ammonia (700:50:1) R_(f) =0.27,FD-MS: M⁺ =499.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(2-naphthylacetyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

105 mg (0.561 mmol) of 2-naphtylacetic acid are reacted in analogy toExample 6 first 92 μl (0.655 mmol) of1-chloro-N,N,2-trimethyl-1-propen-1-amine and subsequently with 200 mg(0.468 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineand 130 μl (0.936 mmol) of triethylamine to give the product TLC:methylene chloride/methanol/conc. ammonia (700:50:1) R_(f) =0.56, FD-MS:M⁺ =595.

EXAMPLE 13

(2R*,4S*)-2-benzyl-1-(4-quinolylmethyl)-N-(4-quinolylmethyl)-4-piperidinamine

128 mg (0.225 mmol) of(2R*,4S*)-2-benzyl-1-(4-quinolylmethyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted with 34 mg (0.872 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR39## is obtained as yellow oil. TLC:methylene chloride/methanol/conc. ammonia (700:50:1) R_(f) =0.45, FD-MS:M⁺ =490.

The starting compound for this is prepared as follows:(2R*,4S*)-2-Benzyl-1-(4-quinolylmethyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

200 mg (0.468 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted in analogy to Example 11 with 88 mg (1.4 mmol) of sodiumcyanoborohydride, 115 mg (1.4 mmol) of sodium acetate, 134 μl (2.34mmol) of acetic acid and 294 mg (1.87 mmol) quinoline-4-carboxaldehydeto give the product. TLC: methylene chloride/methanol/conc. ammonia(700:50:1) R_(f) =0.33, FD-MS: M⁺ =568.

EXAMPLE 14

(2R*,4S*)-2-benzyl-1-(2,4-dichlorobenzyl)-N-(4-quinolylmethyl)-4-piperidinamine

128 mg (0.218 mmol) of (2R*,4S*)-2-benzyl-1-(2,4-dichlorobenzyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted with 34 mg (0.920 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR40## is obtained as yellow oil. TLC:methylene chloride/methanol/conc. ammonia (700:50:1) R_(f) =0.25, FD-MS:M⁺ =472.

The starting compound for this is prepared as follows:

(a)(2R*,4S*)-2-Benzyl-1-(4-quinolylmethyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

200 mg (0.468 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted in analogy to Example 11 with 88 mg (1.4 mmol) of sodiumcyanoborohydride, 115 mg (1.4 mmol) of sodium acetate, 134 μl (2.34mmol) of acetic acid and 294 mg (1.87 mmol) ofquinoline-4-carboxaldehyde to give the product. TLC: methylenechloride/methanol/conc. ammonia (700:50:1) R_(f) =0.33, FD-MS: M⁺ =568.

EXAMPLE 15

(2R*,4S*)-2-benzyl-1-(2,2-diphenylethyl)-N-(4-quinolylmethyl)-4-piperidinamine

170 mg (0.280 mmol) of(2R*,4S*)-2-benzyl-1-(2,2-diphenylethyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted with 42 mg (1.12 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR41## is obtained as white foam. TLC:methylene chloride/methanol/conc. ammonia (1000:50:1) R_(f) =0.28,FD-MS: M⁺ =511.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(2,2-diphenylethyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

200 mg (0.468 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted in analogy to Example 11 with 88 mg (1.4 mmol) of sodiumcyanoborohydride, 115 mg (1.4 mmol) of sodium acetate, 134 μl (2.34mmol) of acetic acid and 335 μl (1.87 mmol) of diphenylacetaldehyde withthe product. TLC: methylene chloride/methanol/conc. ammonia (2000:50:1)R_(f) =0.50, FD-MS: M⁺ =607.

EXAMPLE 16

(2R*,4S*)-2-benzyl-1-(phenylcarbamoyl)-N-(4-quinolylmethyl)-4-piperidinamine

210 mg (0.384 mmol) of(2R*,4S*)-2-benzyl-1-(phenylcarbamoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted with 58 mg (1.54 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR42## is obtained as white foam. TLC:methylene chloride/methanol/conc. ammonia (1000:50:1) R_(f) =0.33,FD-MS: M⁺ =450.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(phenylcarbamoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

A solution of 200 mg (0.468 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineis added to a solution of 72 mg (0.608 mmol) of phenyl isocyanate in 5ml of toluene, and the reaction mixture is stirred at 100° for 2 hours.The white suspension is cooled and filtered. The title compound isobtained as white crystals of melting point 245° (decomposition). TLC:methylene chloride/methanol/conc. ammonia (700:50:1) R_(f) =0.76, FD-MS:M⁺ =546.

EXAMPLE 17

(2R*,4S*)-2-benzyl-1-(diphenylacetyl)-N-(4-quinolylmethyl)-4-piperidinamine

235 mg (0.378 mmol) of(2R*,4S*)-2-benzyl-1-(diphenylacetyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted with 58 mg (1.51 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR43## is obtained as white foam. TLC:methylene chloride/methanol/conc. ammonia (700:50:1) R_(f) =0.49, FD-MS:M⁺ =525.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(diphenylacetyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

248 mg (1.17 mmol) of diphenylacetic acid are reacted in analogy toExample 2j first with 128 μl (1.76 mmol) of thionyl chloride andsubsequently with 200 mg (0.468 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineto give the product. TLC: methylene chloride/methanol/conc. ammonia(700:50:1) R_(f) =0.45, FD-MS: M⁺ =621.

EXAMPLE 18

(2R*,4S*)-2-benzyl-1-(2-pyridylacetyl)-N-(4-quinolylmethyl)-4-piperidinamine

180 mg (0.329 mmol) of(2R*,4S*)-2-benzyl-1-(2-pyridylacetyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted with 50 mg (1.32 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR44## is obtained as white foam. TLC:methylene chloride/methanol/conc. ammonia (700:50:1) R_(f) =0.28, FD-MS:M⁺ =450.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(2-pyridylacetyI)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

200 mg (0.467 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted in analogy to Example 4 with 98 mg (0.561 mmol) of2-pyridylacetic acid hydrochloride, 143 mg (0.562 mmol) ofbis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 209 μl (1.50 mmol) oftriethylamine.

The title compound is obtained as white foam. TLC: methylenechloride/methanol/conc. ammonia (700:50:1) R_(f) =0.60, FD-MS: M⁺ =546.

EXAMPLE 19

(2R*,4S*)-2-benzyl-1-(4-pyridylacetyl)-N-(4-quinolylmethyl)-4-piperidinamine

200 mg (0.366 mmol) of(2R*,4S*)-2-benzyl-1-(4-pyridylacetyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted with 55 mg (1.46 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR45## is obtained as white foam. TLC:methylene chloride/methanol/conc. ammonia (700:50:1) R_(f) =0.31, FD-MS:M⁺ =450.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(4-pyridylacetyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

200 mg (0.468 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted in analogy to Example 4 with 98 mg (0.561 mmol) of4-pyridylacetic acid hydrochloride, 143 mg (0.562 mmol) ofbis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 209 μl (1.50 mmol) oftriethylamine. The title compound is obtained as white foam. TLC:methylene chloride/methanol/conc. ammonia (700:50:1) R_(f) =0.56, FD-MS:M⁺ =546.

EXAMPLE 20

(2R*,4S*)-2-benzyl-1-(2,3-diphenylpropionyl)-N-(4-quinolylmethyl)-4-piperidinamine

340 mg (0.535 mmol) of(2R*,4S*)-2-benzyl-1-(2,3-diphenylpropionyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted with 81 mg (2.14 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR46## is obtained as mixture ofdiastereomers in the form of white foam. TLC: methylenechloride/methanol/conc. ammonia (1000:50:1) R_(f) =0.37, FD-MS: M⁺ =539.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(2,3-diphenylpropionyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

300 mg (0.702 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted in analogy to Example 4 with 190 mg (0.842 mmol) of(R,S)-2,3-diphenylpropionic acid, 214 mg (0.842 mmol) ofbis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 216 μl (1.54 mmol) oftriethylamine. The title compound is obtained as white foam. TLC:methylene chloride/methanol/conc. ammonia (700:50:1) R_(f) =0.74, FD-MS:M⁺ =635.

EXAMPLE 21

(2R*,4S*)-2-benzyl-1-((3S)-(2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-3-yl)carbonyl)-N-(4-quinolylmethyl)-4-piperidinamine

197 mg (0.3 15 mmol) of the mixture of(2R*,4S*)-2-benzyl-1-((3S)-(2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-3-yl)carbonyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinaminediastereomers are reacted with 48 mg (1.26 mmol) of sodium borohydridein analogy to Example 2. The title compound ##STR47## is obtained asmixture of diastereomers in the form of white foam. TLC: methylenechloride/methanol/conc. ammonia (350:50:1) R_(f) =0.50, FD-MS: M⁺ =529.

The starting compounds for this are prepared as follows:

(2R*,4S*)-2-Benzyl-1-((3S)-(2:3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-3-yl)carbonyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

1.97 ml, 19.9 mmol) of piperdine are added to a solution of 338 mg(0.399 mmol) of(2R*,4S*)-2-benzyl-1-((3S)-(2-(9-fluorenylmethyloxycarbonyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-3-yl)carbonyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinaminein 3 ml of N,N-dimethylformamide, and the mixture is stirred at roomtemperature for 2 hours. It is then concentrated in a rotary evaporator,and the residue is chromatographed on silica gel with methylenechloride/methanol/conc. ammonia (2000:50:1) to separate thediastereomers. TLC: methylene chloride/methanol/conc. ammonia(700:50:1).

Diastereomer A: R_(f) =0.21, FD-MS: M⁺ =625,

Diastereomer B: R_(f) =0.13, FD-MS: M⁺ =625.

EXAMPLE 22

(2R*,4S*)-2-benzyl-1-(3-methoxybenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine

230 mg (0.409 mmol) of(2R*,4S*)-2-benzyl-1-(3-methoxybenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted with 81 mg (2.14 mmol) of sodium borohydride in analogy toExample 2. The title compound of the formula ##STR48## is obtained aswhite foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1)R_(f) =0.26, FD-MS: M⁺ =465.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(3-methoxybenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

200 mg (0.468 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted in analogy to Example 4 with 85 mg (0.561 mmol) of3-methoxybenzoic acid, 143 mg (0.561 mmol) ofbis-(2-oxo-3-oxazalidinyl)phosphinic chloride and 144 μl (1.03 mmol) oftriethylamine. The title compound is obtained as white foam. TLC:methylene chloride/methanol/conc. ammonia (1000:50:1) R_(f) =0.45,FD-MS: M⁺ =561.

EXAMPLE 23

(2R*,4S*)-2-benzyl-1-(3-N,N-dimethylaminobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine

225 mg (0.391 mmol) of(2R*,4S*)-2-benzyl-1-(3-N,N-dimethylaminobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted with 59 mg (1.56 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR49## is obtained as white foam. TLC:methylene chloride/methanol/conc. ammonia (700:50:1) R_(f) =0.36, FD-MS:M⁺ =478.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(3-N,N-dimethylaminobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

200 mg (0.468 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted in analogy to Example 4 with 93 mg (0.561 mmol) of3-N,N-dimethylaminobenzoic acid, 143 mg (0.561 mmol) ofbis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 144 μl (1.03 mmol) oftriethylamine. The title compound is obtained as yellow oil. TLC:methylene chloride/methanol/conc. ammonia (1000:50:1) R_(f) =0.65,FD-MS: M⁺ =574.

EXAMPLE 24

(2R*,4S*)-2-benzyl-1-(cis,cis-3,5-dimethylcyclohexylcarbonyl)-N-(4-quinolylmethyl)-4-piperidinamine

195 mg (0.345 mmol) of(2R*,4S*)-2-benzyl-1-(cis,cis-3,5-dimethylcyclohexylcarbonyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted with 52 mg (1.38 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR50## is obtained as white foam. TLC:methylene chloride/methanol/conc. ammonia (1000:50:1) R_(f) =0.24,FD-MS: M⁺ =469.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(cis,cis-3,5-dimethylcyclohexylcarbonyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

200 mg (0.468 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted in analogy to Example 4 with 87 mg (0.561 mmol) ofcis,cis-3,5-dimethylcyclohexylcarboxylic acid (prepared by the method ofH. van Bekkum et. al. (Koninkl. Ned. Akad. Wetenschap, Proc. Ser. B. 64,161 (1961)), 143 mg (0.561 mmol) of bis-(2-oxo-3-oxazolidinyl)phosphinicchloride and 144 μl (1.03 mmol) of triethylamine. The title compound isobtained as yellow oil. TLC: methylene chloride/methanol/conc. ammonia:(1000:50:1) R_(f) =0.32, FD-MS: M⁺ =565.

EXAMPLE 25

(2R*,4S*)-2-benzyl-1-(3,5-bis-(trifluoromethyl)benzyl)-N-(4-quinolylmethyl)-4-piperidinamine

280 mg (28 mmol) of(2R*,4S*)-2-benzyl-1-(3,5-bis-(trifluoromethyl)benzyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted with 65 mg (1.71 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR51## is obtained as white foam. TLC:methylene chloride/methanol/conc. ammonia (1000:50:1) R_(f) =0.35,FD-MS: M⁺ =557.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(3,5-bis-(trifluoromethyl)benzyl)-$N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

A mixture of 129 μl (0.702 mmol) of 3,5-bis-(trifluoromethyl)benzylbromide, 194 mg (1.40 mmol) of potassium carbonate and 300 mg (0.702mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinaminein 3 ml of N,N-dimethylformamide is stirred at 60° for 17 hours. Thesuspension is then filtered, washed thoroughly with acetone, and thefiltrate is concentrated in a rotary evaporator. The residue is taken upin methylene chloride and washed successively with 10% aqueous citricacid, 1N sodiumhydrocarbonate solution, water and brine, and dried overmagnesium sulfate. The yellow oil is chromatographed on silica gel withmethylene chloride/methanol/conc. ammonia (3000:50:1). The tide compoundis obtained as yellow oil. TLC: methylene chloride/methanol/conc.ammonia (3000:50:1) R_(f) =0.36, FD-MS: M⁺ =653.

EXAMPLE 26

2S*,4R*)-2-benzyl-1-[2-(5-chloro-1H-1,2,4-triazol-1-yl)phenoxyethyl]-N-(4-quinolylmethyl)-4-piperidinamine

100 mg (0.54 mmol) of(2R*,4S*)-2-benzyl-1-[2-(5-chlor-1H-1,2,4-triazol-1-yl)phenoxyethyl]-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted with 23 mg (0.62 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR52## is obtained as white foam. TLC:methylene chloride/methanol/conc. ammonia (1000:50:1) R_(f) =0.23,FD-MS: M⁺ =553.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-[2-(5-chlor-1H-1,2,4-triazol-1-yl)phenoxyethyl]-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

200 mg (0.468 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted in analogy to Example 24 with 141 mg (0.468 mmol) of2-(5-chloro-(1H-1,2,4-triazol-1-yl)phenoxy)ethyl bromide and 129 mg(0.936 mmol) of potassium carbonate. The title compound is obtained aswhite foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1)R_(f) =0.23, FD-MS: M⁺ =649.

EXAMPLE 27

Diastereomer A of(2R*,4S*)-2-benzyl-1-((S)-phenylalanyl)-N-(4-quinolylmethyl)-4-piperidinamine

112 mg (0.195 mmol) of diastereomer A of(2R*,4S*)-2-benzyl-1-((S)-phenylalanyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted with 30 mg (0.801 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR53## is obtained as white foam. TLC:methylene chloride/methanol/conc. ammonia (700:50:1) R_(f) =0.21, D-MS:M⁺ =478.

The starting compounds for this are prepared as follows:

a)(2R*,4S*)-2-Benzyl-1-((S)-N-tert.-butyloxycarbonyl-phenylalanyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

300 mg (0.702 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted in analogy to Example 4 with 223 mg (0.842 mmol) of(S)-N-tert.-butyloxycarbonyl-phenylalanine, 214 mg (0.842 mmol) ofbis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 215 μl (1.54 mmol) oftriethylamine. The title compound is obtained as mixture ofdiastereomers in the form of a yellow oil. TLC: methylenechloride/methanol/conc. ammonia (2000:50:1) R_(f) =0.37, FD-MS: M⁺ =674.

b) Diastereomers of(2R*,4S*)-2-benzyl-1-((S)-phenylalanyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

3.1 ml (4.09 mmol) of trifluoroacetic acid are added to 920 mg (1.36mmol) of(2R*,4S*)-2-benzyl-1-((S)-N-tert.-butyloxycarbonyl-phenylalanyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine,and the reaction mixture is stirred at room temperature for 2 hours. Itis then concentrated in a rotary evaporator, the residue is taken up inwater, basified with 1N sodium bicarbonate solution at 0° C. andextracted with methylene chloride. The organic phases are washed withbrine, dried over magnesium sulfate and evaporated to dryness. Theresidue is chromatographed on silica gel with methylenechloride/methanol/conc. ammonia (2500:50:1) to separate thediastereomers. TLC: methylene chloride/methanol/conc. ammonia(1000:50:1).

Diastereomer A: R_(f) =0.24, FD-MS: M⁺ =574,

Diastereomer B: R_(f) =0.22, FD-MS: M⁺ =574.

The mixed fractions of diastereomer A and B were not fractionatedfurther.

EXAMPLE 28

Diastereomer B of(2R*,4S*)-2-benzyl-1-((S)-phenylalanyl)-N-(4-quinolylmethyl)-4-piperidinamine

115 mg (0.200 mmol) of diastereomer B of(2R*,4S*)-2-benzyl-1-((S)-phenylalanyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted with 30 mg (0.801 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR54## is obtained as white foam. TLC:methylene chloride/methanol/conc. ammonia (700:50:1) R_(f) =0.20, FD-MS:M⁺ =478.

See Example 27a for the starting compound for this.

EXAMPLE 29

Diastereom A of(2R*,4S*)-2-benzyl-1-((R)-phenylalanyl)-N-(4-quinolylmethyl)-4-piperidinamine

174 mg (0.303 mmol) of diastereomer A of(2R*,4S*)-2-benzyl-1-((R)-phenylalanyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted with 46 mg (1.211 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR55## is obtained as white foam. TLC:methylene chloride/methanol/conc. ammonia (700:50:1) R_(f) =0.28, D-MS:M⁺ =478.

The starting compounds for this are prepared as follows:

Diastereomers of(2R*,4S*)-2-benzyl-1-((R)-phenylalanyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

1.10 g (1.63 mmol) of(2R*,4S*)-2-benzyl-1-((R)-N-tert.-butyloxycarbonyl-phenylalanyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare treated with 3.8 ml (48.8 mmol) of trifluoroacetic acid in analogyto Example 27b. The diastereomers of the title compound are obtained.TLC: methylene chloride/methanol/conc. ammonia (1000:50:1).

Diastereomer A: R_(f) =0.52, FD-MS: M⁺ =574,

Diastereomer B: R_(f) =0.50, FD-MS: M⁺ =574.

The mixed fractions of diastereomer A and B are not fractionatedfurther.

EXAMPLE 30

Diastereomer B of(2R*,4S*)-2-benzyl-1-((R)-phenylalanyl)-N-(4-quinolylmethyl)-4-piperidinamine

92 mg (0.160 mmol) of diastereomer B of(2R*,4S*)-2-benzyl-1-((R)-phenylalanyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted with 25 mg (0.640 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR56## is obtained as white foam. TLC:methylene chloride/methanol/conc. ammonia (350:50:1) R.sub. 0.49, FD-MS:M⁺ =478.

See Example 27a for the starting compound for this.

EXAMPLE 31

(2R*,4S*)-2-benzyl-1-((S)-N-acetyl-phenylalanyl)-N-(4-quinolylmethyl)-4-piperidinamine

160 mg (0.259 mmol) of the mixture of(2R*,4S*)-2-benzyl-1-((S)-N-acetyl-phenylalanyl)N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinaminediastereomers are reacted with 39 mg (1.04 mmol) of sodium borohydridein analogy to Example 2. The title compound ##STR57## is obtained asmixture of diastereomers as white foam. TLC: methylenechloride/methanol/conc. ammonia (1000:50:1) R_(f) =0.22, FD-MS: M⁺ =520.

The starting compound for this are prepared as follows:

(2R*,4S*)-2-Benzyl-1-((S)-N-acetyl-phenylalanyl)N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

35 μl (0.376 mmol) of acetic anhydride are added to a solution of 180 mg(0.313 mmol) of the mixture of(2R*,4S*)-2-benzyl-1-((S)-phenylalanyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinaminediastereomers in 2 ml pyridine at 0°, and the mixture is stirred at 0°for 2.5 hours. The oily residue after evaporation in a rotary evaporatoris taken up in methylene chloride, washed with 5% aqueous citric acidand with 1N sodium bicarbonate solution. The organic phases are driedover magnesium sulfate and evaporated to dryness. The title compound isobtained as white foam. TLC: methylene chloride/methanol/conc. ammonia(1000:50:1) R_(f) =0.39, FD-MS: M⁺ =616.

EXAMPLE 32

(2R*,4S*)-2-benzyl-1-((R)-N-acetyl-phenylalanyl)-N-(4-quinolylmethyl)-4-piperidinamine

185 mg (0.411 mmol) of the mixture of(2R*,4S*)-2-benzyl-1-((R)-N-acetyl-phenylalanyl)N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinaminediastereomers are reacted with 62 mg (1.64 mmol) of sodium borohydridein analogy to Example 2. The title compound ##STR58## is obtained asmixture of diastereomers (white foam). TLC: methylenechloride/methanol/conc. ammonia (700:50:1) R_(f) =0.42, FD-MS: M⁺ =520.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-((R)-N-acetyl-phenylalanyl)N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

920

200 mg 0.348 mmol) of the mixture of(2R*,4S*)-2-benzyl-1-((R)-phenylalanyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinaminediastereomers are reacted with 39 μl (0.417 mmol) of acetic anhydride inanalogy to Example 31. The title compound is obtained as mixture ofdiastereomers (white foam). TLC: methylene chloride/methanol/conc.ammonia (1000:50:1) R_(f) =0.28, FD-MS: M⁺ =616.

EXAMPLE 33

(2R*,4S*)-2-benzyl-1-((S)-N-(4-carboxamido-butyroyl)phenylalanyl)-N-(4-quinolylmethyl)-4-piperidinamine

152 mg (0.221 mmol) of the mixture of(2R*,4S*)-2-benzyl-1-((S)-N-(4-carboxamido-butyroyl)phenylalanyl)N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted with 34 mg (0.88 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR59## is obtained as mixture ofdiastereomers as white foam. TLC: methylene chloride/methanol/conc.ammonia (350:50:1) R_(f) =0.50, B-MS: M⁺ =591.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-((S)-N-(4-carboxamido-butyroyl)phenylalanyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

179 μl (1.04 mmol) of diisopropylethylamine and 108 mg (0.348 mmol) ofglutaric acid mono-2,4,5-trichlorophenyl ester amide are added to asolution of 200 mg (0.348 mmol) of the mixture of(2R*,4S*)-2-benzyl-1-((S)-phenylalanyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinaminediastereomers in 2 ml of methylene chloride at 0°, and the whitesuspension is stirred at 0° for 2 hours and at room temperature for 16hours. The solution, which is now colourless, is concentrated in arotary evaporator, and the oily residue is then taken up in methylenechloride, washed with 5% aqueous citric acid and with 1N sodiumbicarbonate solution. The organic phases are dried over magnesiumsulfate and evaporated to dryness. The title compound is obtained aswhite foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1)R_(f) =0.13, D-MS: M⁺ =687.

EXAMPLE 34

(2R*,4S*)-2-benzyl-1-((R)-N-(4-carboxamido-butyroyl)phenylalanyl)-N-(4-quinolylmethyl)-4-piperidinamine

210 mg (0.305 mmol) of the mixture of(2R*,4S*)-2-benzyl-1-((R)-N-(4-carboxamido-butyroyl)phenylalanyl)N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted with 46 mg (1.22 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR60## is obtained as mixture ofdiastereomers as white foam. TLC: methylene chloride/methanol/conc.ammonia (350:50:1) R_(f) =0.56, FD-MS: M⁺ =591.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-[(R)-N-(4-carboxamido-butyroyl)phenylalanyl]-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

222 mg (0.386 mmol) of the mixture of(2R*,4S*)-2-benzyl-1-[(R)-phenylalanyl)-N-(4-quinolylmethyl]-N-trifluoroacetyl-4-piperidinaminediastereomers are reacted in analogy to Example 33 with 198 μl (1.16mmol) of diisopropylethylamine and 120 mg (0.386 mmol) of glutaric acidmono-2,4,5-trichlorophenyl ester amide. The title compound is obtainedas mixture of diastereomers as white foam. TLC: methylenechloride/methanol/conc. ammonia (700:50:1) R_(f) =0.38, FD-MS: M⁺ =687.

EXAMPLE 35

(2R*,4S*)-2-benzyl-1-benzoyl-N-(4-quinolylmethyl)-4-piperidinamine

234 mg (0.440 mmol) of(2R*,4S*)-2-benzyl-1-benzoyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted with 67 mg (1.76 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR61## is obtained as white foam. TLC:methylene chloride/methanol/conc. ammonia (700:50:1) R_(f) =0.33, FD-MS:M⁺ =435.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-benzoyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

72 μl (0.515 mmol) of triethylamine and 54 μl (0.468 mmol) of benzoylchloride are added to a solution of 200 mg (0.468 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinaminein 4 ml of methylene chloride. The reaction mixture is stirred at 0° for3 hours, water is added, extraction with methylene chloride is carriedout. The organic phases are dried over magnesium sulfate and evaporatedto dryness. The yellow oil is chromatographed on silica gel withmethylene chloride/methanol/conc. ammonia (1000:50:1). The titlecompound is obtained as white foam. TLC: methylenechloride/methanol/conc. ammonia (700:50:1) R_(f) =0.72, FD-MS: M⁺ =531.

EXAMPLE 36

(2R*,4S*)-2-benzyl-1-(3-chlorobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine

254 mg (0.449 mmol) of(2R*,4S*)-2-benzyl-1-(3-chlorobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted with 68 mg (1.80 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR62## is obtained as white foam. TLC:methylene chloride/methanol/conc. ammonia (700:50:1) R_(f) =0.29, FD-MS:M⁺ =470.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(4-chlorobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

200 mg (0.468 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted in analogy to Example 35 with 72 μl (0.5 15 mmol) oftriethylamine and 60 μl (0.468 mmol) of 3-chlorobenzoyl chloride to givethe product. TLC: methylene chloride/methanol/conc. ammnonia (700:50:1)R_(f) =0.71, FD-MS: M⁺ =566.

EXAMPLE 37

(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylmethyl)-N-(3-carboxamidopropionyl)-4-piperidinamine

92 mg (0.99 mmol) of 1-hydroxybenzotriazole and 138 mg (0.899 mmol) ofN,N'-dicyclohexylcarbodiimide are added to a solution of 181 mg (0.299mmol) of(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylmethyl)-N-(3-carboxypropionyl)-4-piperidinaminein 2 ml of tetrahydrofuran. Stirring at room temperature for half anhour is followed by addition of 2.1 ml (15 mmol) of a 7M solution ofammonia in ethanol and stirring at room temperature for 36 hours. Theresidue from evaporation in a rotary evaporator is suspended inmethylene chloride/ether (1:1), and the white suspension is filtered.The filtrate is concentrated in a rotary evaporator, and the yellow oilis chromatographed on silica gel with methylene chloride/methanol/conc.ammonia (1000:50:1). The title compound ##STR63## is obtained as whitesolid substance. TLC: methylene chloride/methanol/conc. ammonia(700:50:1) R_(f) =0.23, FD-MS: M⁺ =602, 604.(2R*,4S*)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylmethyl)-N-(3-N-cyclohexyl-carbamidopropionyl)-4-piperidinamineis obtained as by product from the chromatography. TLC: methylenechloride/methanol/conc. ammonia (700:50:1) R_(f) =0.40, FD-MS: M⁺ =684,686.

EXAMPLE 38

(2R,4S)-2-benzyl-1-(3,5-bis-(trifluoromethyl)benzoyl)-N-(4-quinolylmethyl)-4-piperidinamine

3.35 g (7.78 mmol) of(2R,4S)-2-benzyl-1-(3,5-bis-(trifluoromethyl)benzoyl)-4-piperidinamineare reacted in analogy to Example 2 g with 1.34 g (8.56 mmol) ofquinoline-4-carboxaldehyde and 1.3 g of magnesium sulfate in 30 ml oftoluene, and subsequently reduced with 324 mg (8.56 mmol) of sodiumborohydride in 25 ml of methanol. The title compound ##STR64## isobtained (3.5 g, 79%) as white foam. TLC: methylenechloride/methanol/conc. ammonia (1000:50:1) R_(f) =0.21, FD-MS: M⁺ =571,[α]_(D) =+0.7 (c=1, MeOH), IR: 1635 cm⁻.

The starting compound for this is prepared as follows:

a) (2R,4R)-2-Benzyl-1-t-butyloxycarbonyl-4-hydroxypiperidine

24 g (111 mmol) of (-)-camphanic chloride are added to a solution of26.9 g (92.3 mmol) of(2R*,4R*)-2-benzyl-1-t-butyloxycarbonyl-4-hydroxypiperidine in 200 ml ofpyridine at 0 ° C., and the mixture, which becomes heterogeneous, isstirred at 0° C. for 2 hours and subsequently at RT for 16 hours. Afterconcentration in a rotary evaporator, the reaction mixture is taken upin methylene chloride, washed twice with 10% citric acid, once withwater and once with brine, dried over magnesium sulfate and evaporatedin a rotary evaporator. 47.8 g of the diastereomeric mixture of thecamphanic esters are obtained as orange oil. Diastereomer A: R_(f)=0.52; Diastereomer B: R_(f) =0.47. The latter is chromatographed onsilica gel with toluene/ethyl acetate (9:1), and the diastereomericesters are crystallised from hexane. Diastereomer A is obtained as whitecrystals (14.2 g, 33%); melting point: 114°-115 ° C. and diastereomer Bas white crystals (15.3 g, 35%); melting point: 138°-139 ° C.

130 ml of 0.5N sodium hydroxide solution are added to a solution ofdiastereomer B in 300 ml of methanol, and the reaction mixture isstirred at RT for 18 hours. After concentration in a rotary evaporator,the reaction mixture is taken up in methylene chloride, washed withwater and brine, dried over magnesium sulfate and evaporated in a rotaryevaporator. The title compound is obtained as yellow oil (9.3 g, 98%).TLC: toluene/ethyl acetate (7:3) R_(f) =0.34, FD-MS: M⁺ =291, [α]_(D)=+32° (c=1, Methanol).

b)(2R,4R)-2-Benzyl-1-t-butyloxycarbonyl-4-(O-methylsulfonyl)-hydroxypiperidine

9.3 g (32 mmol) of(2R,4R)-2-benzyl-1-t-butyloxycarbonyl-4-hydroxypiperidine are reactedwith 5 ml (63.8 mmol) of methanesulfonyl chloride in 10 ml of pyridinein analogy to Example 2d. The title compound (11 g, 93%) is obtained ascolourless needles. Melting point: 137 ° C., TLC: toluene/ethyl acetate(4:1) R_(f) =0.42, [α]_(D) =+21° (c=1, MeOH).

c) (2R,4S)-2-Benzyl-1-t-butyloxycarbonyl-4-piperidine azide

10.9 g (29.6 mmol) of(2R,4R)-2-benzyl-1-t-butyloxycarbonyl-4-(O-methylsulfonyl)-hydroxypiperidineare reacted with 1.6 g (32.6 mmol) of lithium azide in 60 ml ofN,N-Dimethylformamide in analogy to Example 2e. The title compound isobtained mixed with2-benzyl-N-t-butyloxycarbonyl-1,2,5,6-tetrahydropyridine (9.2 g, ratioby weight according to NMR: 4.7:1), which is not fractionated further.TLC: toluene/ethyl acetate (9:1) R_(f) =0.59.

d) (2R,4S)-2-Benzyl-4-piperidine azide

A mixture from Example 38c (calculated content of(2R,4S)-2-benzyl-1-t-butyloxycarbonyl-4-piperidine azide: 7.58 g (80%))is mixed with 36 ml of trifluoroacetic acid and stirred at RT for 90minutes. It is then concentrated in a rotary evaporator, the residue istaken up in methylene chloride and washed with 2N sodium hydroxidesolution. The organic phases are dried over magnesium sulfate andevaporated to dryness. The residue is chromatographed on silica gel withmethylene chloride/methanol/conc. ammonia (1000:50:1). The titlecompound (4.7 g, 92%) is obtained as yellow oil. TLC: methylenechloride/methanol/conc. ammonia (350:50:1) R_(f) =0.63, IR: 2100 cm⁻¹,[α]_(D) =-28.8° (c=1, Methanol).

e) (2R,4S)-2-Benzyl-1-(3,5-bis-(trifluoromethyl)benzoyl)-4-piperidineazide

2.2 g (10.2 mmol) of (2R,4S)-2-benzyl-4-piperidine azide are reacted inanalogy to Example 4a with 2.5 g (12.2 mmol) of3,5-bis-(trifluoromethyl)benzoic acid, 3.I g (12.2 mmol) ofbis(2-oxo-3-oxazolidinyl)phosphinic chloride and 3.1 ml (22.4 mmol) oftriethylamine. The title compound (4.16 g, 90%) is obtained as yellowoil. TLC: toluene/ethyl acetate (9:1) R_(f) =0.45, FD-MS: M⁺ =456,[α]_(D) =+5.1° (c-1, Methanol).

f)(2R,4S)-2-Benzyl-1-(3,5-bis-(trifluoromethyl)benzoyl)-4-piperidinamine

4.1 g (9.0 mmol) of(2R,4S)-2-benzyl-1-(3,5-bis-(trifluoromethyl)benzoyl)-4-piperidine azideare hydrogenated with 10% Pd/C in analogy to Example 2f. The titlecompound (3.38 g, 87%) is obtained as oil. TLC: methylenechloride/methanol/conc. ammonia (350:50:1) R_(f) =0.47, FD-MS: M⁺ =430,[α]_(D) =-3.0° (c=1, Methanol).

EXAMPLE 39

(2R,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine

1.95 g (5.37 mmol) of(2R,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reacted inanalogy to Example 2g with 0.93 g (5.90 mmol) ofquinoline-4-carboxaldehyde and 0.9 g of magnesium sulfate in 18 ml oftoluene and subsequently reduced with 223 mg (5.90 mmol) of sodiumborohydride in 18 ml of methanol. The title compound ##STR65## isobtained (2.2 g, 82%) as white foam. TLC: methylenechloride/methanol/conc. ammonia (700:50:1) R_(f) =0.35, FD-MS: M⁺ =503,505, [α]_(D) =19.3 (c=l, MeOH), IR: 1635, 1595, 1565 cm⁻¹.

The starting compound for this is prepared as follows:

a) (2R,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-4-piperidine azide

A solution of 2.8 g (13.3 mmol) of 3,5-dichlorobenzoyl chloride is addeddropwise to a solution of 2.4 g (11.1 mmol) of(2R,4S)-2-benzyl-4-piperidine azide and 2.2 ml (15.5 mmol) ofMethylamine in 35 ml of methylene chloride at 0° C. Stirring at 0° C.for 18 hours is followed by concentration in a rotary evaporator, andthe yellow oil is partitioned between methylene chloride and water. Theorganic phases are washed with brine, dried over magnesium sulfate andevaporated to dryness. The resulting oil is chromatographed on silicagel with toluene/ethyl acetate (9:1). The title compound (4.04 g, 94%)is obtained as semicrystalline mass. TLC: toluene/ethyl acetate (9:1)R_(f) =0.51; FD-MS: M⁺ =388, 390; [α]_(D) =+33.4° (c=1, MeOH).

b) (2R,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine

4.02 g (10.3 mmol) of(2R,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidine azide arehydrogenated with 10% Pd/C in analogy to Example 2f. The title compound(1.97 g, 52%) is obtained as oil. TLC: methylene chloride/methanol/conc.ammonia (350:50:1) R_(f) =0.40, FD-MS: M⁺ =362, 364; IR: 3660, 3360,1630 cm⁻¹ ; [α]_(D) =+22.7° (c=1, Methanol).

EXAMPLE 40

(2R*,4S*)-2-benzyl-1-(2,4-dichlorobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine

A solution of 195 mg (0.325 mmol) of(2R*,4S*)-2-benzyl-1-(2,4-dichlorobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineand 26 mg (0.649 mmol) of sodium hydroxide in 2 ml of methanol and 2 mlof tetrahydrofuran is left to stir at 0° C. for 18 hours. The reactionmixture is then concentrated, taken up in methylene chloride and washedwith water and brine. The organic phases are dried over magnesiumsulfate and evaporated to dryness. The yellow oil is chromatographed onsilica gel with methylene chloride/methanol/conc. ammonia (800:50:1).The title compound ##STR66## is obtained (157 mg, 96%) as white foam.TLC: methylene chloride/methanol/conc. ammonia (700:50:1) R_(f) =0.45,FD-MS: M⁺ =503,505.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(2,4-dichlorobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

200 mg (0.468 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted in analogy to Example 35a with 91 μl (0.655 mmol) oftriethylamine and 78 μl (0.561 mmol) of 2,4-dichlorobenzoyl chloride togive the title compound (240 mg, 86%). TLC: methylenechloride/methanol/conc. ammonia (700:50:1) R_(f) =0.57, FD-MS: M⁺ =599,601.

EXAMPLE 41

(2R*,4S*)-2-benzyl-1-(phenylacetyl)-N-(4-quinolylmethyl)-4-piperidinamine

192 mg (0.352 mmol) of(2R*,4S*)-2-benzyl-1-(2-phenylacetyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted in analogy to Example 40 with 141 μl (0.704 mmol) of 5Nsodium hydroxide solution in 1 ml of tetrahydrofuran and 1 ml ofmethanol. The title compound ##STR67## is obtained (73 mg, 46%) as whitefoam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) R_(f)=0.43, FD-MS: M⁺ =449.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(phenylacetyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

200 mg (0.468 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted in analogy to Example 35a with 72 μl (0.5 15 mmol) oftriethylamine and 62 μl (0.468 mmol) of phenylacetyl chloride to givethe title compound (208 mg, 81%). TLC: methylene chloride/methanol/conc.ammonia (700:50:1) R_(f) =0.54, FD-MS: M⁺ =545.

EXAMPLE 42

(2R*,4S*)-2-benzyl-1-(2,6-dichlorobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine

138 mg (0.230 mmol) of(2R*,4S*)-2-benzyl-1-(2,6-dichlorobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted in analogy to Example 40 with 18.4 mg (0.460 mmol) of sodiumhydroxide in 1.5 ml of tetrahydrofuran and 1.5 ml of methanol. The titlecompound ##STR68## is obtained (56 mg, 48%) as white foam. TLC:methylene chloride/methanol/conc. ammonia (700:50:1) R_(f) =0.50, FD-MS:M⁺ =503,505.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(2,6-dichlorobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

200 mg (0.468 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted in analogy to Example 35a with 91 μl (0.655 mmol) oftriethylamine and 80 μl (0.561 mmol) of 2,6-dichlorobenzoyl chloride togive the title compound (I 58 mg, 56%). TLC: methylenechloride/methanol/conc. ammonia (700:50:1) R_(f) =0.62, FD-MS: M⁺=599,601.

EXAMPLE 43

(2R*,4S*)-2-Benzyl-1-(3,5-dibromobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine

0.166 g (0.241 mmol) of(2R*,4S*)-2-benzyl-1-(3,5-dibromobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineis reacted with 0.037 g (0.96 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR69## is obtained (0.094 g, 66%) aswhite foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1)R_(f) =0.23, FD-MS: M⁺ =591,593, 595.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(3,5-dibromobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

197 mg (0.70 mmol) of 3,5-dibromobenzoic acid (prepared according to J.Organometallic Chem. 215, 281 (1981)) are reacted in analogy to Example2a first with 2 ml (27 mmol) of thionyl chloride and subsequently with200 mg (0.468 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineand 130 μl (0.936 mmol) of triethylamine to give the title compound (168mg, 52%). TLC: methylene chloride/methanol/conc. ammonia (700:50:1)R_(f) =0.60, FD-MS: M⁺ =687, 689, 691.

EXAMPLE 44

(2R*,4S*)-2-benzyl-1-(9-fluorenoyl)-N-(4-quinolylmethyl)-4-piperidinamine

0.238 g (0.384 mmol) of(2R*,4S*)-2-benzyl-1-(9-fluorenoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineis reacted with 0.066 g (1.54 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR70## is obtained (0.155 g, 79%) aswhite foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1)R_(f) =0.36, FD-MS: M⁺ =523.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(9-fluorenoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

200 mg (0.467 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted in analogy to Example 4a with 78 mg (0.562 mmol) of9-fluorene carboxylic acid, 143 mg (0.561 mmol) ofbis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 144 μl (1.03 mmol) oftriethylamine. The title compound (241 mg, 82%) is obtained as oil. TLC:methylene chloride/methanol/conc. ammonia (1000:50:1) R_(f) =0.58,FD-MS: M⁺ =619.

EXAMPLE 45

(2R*,4S*)-2-benzyl-1-(3-toluoyl)-N-(4-quinolylmethyl)-4-piperidinamine

0.25 1 g (0.460 mmol) of(2R*,4S*)-2-benzyl-1-(3-toluoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineis reacted with 0.070 g (1.84 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR71## is obtained (0.172 g, 83%) aswhite foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1)R_(f) =0.27, D-MS: M⁺ =449.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(3-toluoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

96 mg (0.70 mmol) m-toluic acid are reacted in analogy to Example 2 afirst with 2 ml (27 mmol) of thionyl chloride and subsequently with 200mg (0.468 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineand 118 μl (0.842 mmol) of triethylamine to give the title compound (251mg, 98%). TLC: methylene chloride/methanol/conc. ammonia (700:50:1)R_(f) =0.51, FD-MS: M⁺ =545.

EXAMPLE 46

(2R*,4S*)-2-benzyl-1-(3-bromobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine

0.271 g (0.444 mmol) of(2R*,4S*)-2-benzyl-1-(3-bromobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineis reacted with 0.067 g (1.78 mol) of sodium borohydride in analogy toExample 2. The title compound ##STR72## is obtained (0.212 g, 93%) asoil. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) R_(f)=0.29, FD-MS: M⁺ =513, 515.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(3-bromobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

141 mg (0.70 mmol) of m-bromobenzoic acid are reacted in analogy toExample 2a first with 2 ml (27 mmol) of thionyl chloride andsubsequently with 200 mg (0.468 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineand 118 μl (0.842 mmol) of triethylamine to give the title compound (271mg, 95%). TLC: methylene chloride/methanol/conc. ammonia (700:50:1)R_(f) =0.7I, FD-MS: M⁺ =609, 611.

EXAMPLE 47

(2R*,4S*)-2-benzyl-1-(3,5-dihydroxybenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine

0.097 g (0.172 mmol) of(2R*,4S*)-2-benzyl-1-(3,5-dihydroxybenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineis reacted with 0.026 g (0.688 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR73## is obtained (0.023 g, 29%) aswhite foam. TLC: methylene chloride/methanol/conc. ammonia (350:50:1)R_(f) =0.57, FD-MS: M⁺ =467.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(3,5-dihydroxybenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

200 mg (0.467 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted in analogy to Example 4a with 87 mg (0.562 mmol) of3,5-dihydroxybenzoic acid, 143 mg (0.561 mmol)ofbis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 144 μl (1.03 mmol) oftriethylamine. The title compound (99 mg, 38%) is obtained as whitefoam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) R_(f)=0.41, FD-MS: M⁺ =563.

EXAMPLE 48

(2R*,4S*)-2-benzyl-1-(3-cyanobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine

0.248 g (0.446 mmol) of(2R*,4S*)-2-benzyl-1-(3-cyanobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineis reacted with 0.068 g (1.78 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR74## is obtained (0.157 g, 62%) aswhite foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1)R_(f) =0.51, FD-MS: M⁺ =460.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(3-cyanobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

200 mg (0.467 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted in analogy to Example 4a with 69 mg (0.514 mmol) of3-cyanobenzoic acid, 143 mg (0.561 mmol) ofbis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 144 μl (1.03 mmol) oftriethylamine. The title compound (250 mg, 96%) is obtained as whitefoam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) R_(f)=0.53, FD-MS: M⁺ =556.

EXAMPLE 49

(2R*,4S*)-2-benzyl-1-(2-chlorobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine

0.165 g (0.291 mmol) of(2R*,4S*)-2-benzyl-1-(2-chlorobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineis reacted with 0.044 g (1.16 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR75## is obtained (0.109 g, 80%) aswhite foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1)R_(f) =0.33, MS: M⁺ =469, 471; IR: 3680, 1640, 1605, 1580 cm⁻¹.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(2-chlorobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

200 mg (0.467 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted in analogy to Example 4a with 88 mg (0.560 mmol) of2-chlorobenzoic acid, 143 mg (0.561 mmol) ofbis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 144 μl (1.03 mmol) oftriethylamine. The title compound (179 mg, 68%) is obtained as whimfoam. TLC: methylene chloride/methanol/conc. ammonia (2000:50:1) R_(f)=0.42, FD-MS: M⁺ =565, 567.

EXAMPLE 50

(2R*,4S*)-2-benzyl-1-(4-chlorobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine

0.202 g (0.291 mmol) of(2R*,4S*)-2-benzyl-1-(4-chlorobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineis reacted with 0.054 g (1.43 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR76## is obtained (0.136 g, 81%) aswhite foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1)R_(f) =0.17, FD-MS: M⁺ =469, 471; IR: 3675, 1625, 1595, 1570 cm⁻¹.

The starting compound for this is prepared as follows:(2R*,4S*)-2-Benzyl-1-(4-chlorobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

200 mg (0.467 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted in analogy to Example 4a with 88 mg (0.560 mmol) of4-chlorobenzoic acid, 143 mg (0.561 mmol)bis(2-oxo-3-oxazolidinyl)phosphinic chloride and 144 μl (1.03 mmol) oftriethylamine. The title compound (210 mg, 80%) is obtained as whitefoam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) R_(f)=0.44, FD-MS: M⁺ =565, 567.

EXAMPLE 51

(2R*,4S*)-2-benzyl-1-(9-fluorenyl)-N-(4-quinolylmethyl)-4-piperidinamine

130 mg (0.219 mmol)(2R*,4S*)-2-benzyl-1-(9-fluorenyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted in analogy to Example 40 with 500 μl (0.500 mmol) of 1Nsodium hydroxide solution in 1 ml of tetrahydrofuran and 1 ml ofmethanol. The title compound ##STR77## is obtained (49 mg, 45%) as whitefoam. TLC:toluene/ethyl acetate (1:1) R_(f) =0.26; FD-MS:M⁺ =495.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(9-fluorenyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

200 mg (0.467 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineare reacted in analogy to Example 25a with 138 mg (0.561 mmol) of9-bromofluorene and 155 mg (1.12 mmol) of potassium carbonate in 2.5 mlof acetone. The title compound (131 mg, 47%) is obtained as oil.TLC:toluene/ethyl acetate (1:1) R_(f) =0.43; FD-MS:M⁺ =591.

EXAMPLE 52(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylmethyl)-N-methyl-4-piperidinamine

13.4 mg (0.446 mmol) of an 80% strength suspension of sodium hydride inmineral oil (suspended in hexane and decanted) are added in one portionto a solution of 150 mg (0.297 mmol) of(2S*,4R*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylmethyl)-4-piperidinaminein 2 ml of 1,2-dimethoxyethane at 0° C. After 10 minutes at 0° C., themixture is left to stir at RT for 30 minutes, again cooled to 0° C., and22 μl (0.357 mmol) of methyl iodide are added. The mixture is thenstirred at RT for 96 hours. The solvent is stripped off in a rotaryevaporator, and the residue is chromatographed on silica gel withtoluene/ethyl acetate (1:1). The title compound ##STR78## is obtained(20 mg, 13%) as white foam. TLC:toluene/ethyl acetate (1:1) R_(f) =0.45;FD-MS:M⁺ =517, 519.

EXAMPLE 53 (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylmethyl)-N-cyclohexylcarbamoy-4-piperidinamine

200 mg (0.396 mmol) of(2S*,4R*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamineare reacted with 66 μl (0.515 mmol) of cyclohexyl isocyanate in analogyto Example 16a. The title compound ##STR79## is obtained as whitecrystals (165 mg, 66%) of melting point 229° C. (decomposition).TLC:methylene chloride/methanol/conc. ammonia (700:50: 1) R_(f) =0.44,FD-MS:M⁺ =628, 630.

EXAMPLE 54(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylmethyl)-N-phenylcarbamoy-4-piperidinamine

200 mg (0.396 mmol) of(2S*,4R*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamineare reacted with 45 mg (0.377 mmol) of phenyl isocyanate in analogy toExample 16a. The title compound ##STR80## is obtained as solid residue(129 mg, 52%). TLC:methylene chloride/methanol/conc. ammonia (700:50:1)R_(f) =0.42, FD-MS:M⁺ =622, 624.

EXAMPLE 55(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(2-phenylethyl)-4-piperidinamine

0.130 g (0.231 mmol) of(2R*,45*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(2-phenylethyl)-N-trifluoroacetyl-4-piperidinamineis reacted with 0.035 g (0.923 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR81## is obtained (0.101 g, 94%) asoil. TLC:methylene chloride/methanol/conc. ammonia (700:50:1) R_(f)=0.34, FD-MS:M⁺ =466, 468.

The starting compound for this is prepared as follows:

a)(2R*,4S*)-2-Benzyl-1-t-butyloxycarbonyl-N-(2-phenylethyl)-4-piperidinamine

1 g (3.44 mmol) of(2R*,4S*)-2-benzyl-1-t-butyloxycarbonyl-4-piperidinamine is reacted inanalogy to Example 11a with 1 ml (4.48 mmol) of phenylacetaldehyde,0.433 g (6.89 mmol) of sodium cyanoborohydride, 0.791 g (9.64 mmol) ofsodium acetate and 434 μl of acetic acid to give the title compound (805mg, 60%). TLC:methylene chloride/methanol/cone. ammonia (700:50:1) R_(f)=0.35, FD-MS:M⁺ =394.

b)(2R*,4S*)-2-Benzyl-1-t-butyloxycarbonyl-N-(2-phenylethyl)-N-trifluoroacetyl-4-piperidinamine

618 mg (1.57 mmol) of(2R*,4S*)-2-benzyl-1-t-butyloxycarbonyl-N-(4-quinolylmethyl)-4-piperidinamineare reacted in analogy to Example 2h with 240 μl (1.72 mmol) oftrifluoroacetic anhydride and 284 μl (2.04 mmol) of triethylamine. Thetitle compound is obtained as white foam (572 mg, 75%).TLC:toluene/ethyl acetate (9:1) R_(f) =0.47, FD-MS:(M+H)⁺ =491.

c)(2R*,4S*)-2-Benzyl-N-(2-phenylethyl)-N-trifluoroacetyl-4-piperidinamine615 mg (1.25 mmol) of(2R*,4S*)-2-benzyl-1-t-butyloxycarbonyl-N-(2-phenylethyl)-N-trifluoroacetyl-4-piperidinamineare reacted with 1.9 ml (25 mmol) of trifluoroacetic acid in analogy toExample 38d. The title compound is obtained as oil (308 mg, 63%).TLC:methylene chloride/methanol/cone. ammonia (700:50:1) R_(f) =0.63,FD-MS:M⁺ =390.

d)(2R*,4S*)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-(2-phenylethyl)-N-trifluoroacetyl-4-piperidinamine

189 mg (0.992 mmol) of 3,5-dichlorobenzoic acid are reacted in analogyto Example 2a first with 0.108 ml (1.49 mmol) of thionyl chloride andsubsequently with 155 mg (0.397 mmol) of(2R*,4S*)-2-benzyl-N-(2-phenylethyl)-N-trifluoroacetyl-4-piperidinamineand 166 μl (1.19 mmol) of triethylamine to give the title compound (135mg, 60%). TLC:methylene chloride/methanol/cone. ammonia (1000:50:1)R_(f) =0.70, FD-MS:M⁺ =562, 564.

EXAMPLE 56(2R*,4S*)-2-benzyl-1-(3,5-bis(trifluoromethyl)benzoyl)-N-(2-phenylethyl)-4-piperidinamine

0.190 g (0.301 mmol) of(2R*,4S*)-2-benzyl-1-(3,5-bis(trifluoromethyl)benzoyl)-N-(2-phenylethyl)-N-trifluoroacetyl-4-piperidinamineis reacted with 0.046 g (1.21 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR82## is obtained (0.123 g, 76%) asoil. TLC:methylene chloride/methanol/cone. ammonia (1000:50:1) R_(f)=0.22, FD-MS:M⁺ =534, IR:1630 cm⁻.

The starting compound for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(3,5-bis(trifluoromethyl)benzoyl)-N-(2-phenylethyl)-N-trifluoroacetyl-4-piperidinamine

150 mg (0.384 mmol) of(2R*,4S*)-2-benzyl-N-(2-phenylethyl)-N-trifluoroacetyl-4-piperidinamineare reacted in analogy to Example 4a with 93 mg (0.461 mmol) of3,5-bis(trifluoromethyl)benzoic acid, 117 mg (0.461 mmol) ofbis(2-oxo-3-oxazolidinyl)phosphinic chloride and 118 μl (0.845 mmol) oftriethylamine. The title compound (191 mg, 79%) is obtained as oil.TLC:methylene chloride/methanol/cone. ammonia (2000:50:1) R_(f) =0.79,FD-MS:M⁺ =630.

EXAMPLE 57(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(2-naphthoyl)-4-piperidinamine

142 mg (0.825 mmol) of 2-naphthoic acid are reacted in analogy toExample 2a first with 2 ml (27 mmol) of thionyl chloride andsubsequently with 200 mg (0.550 mmol) of(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine and 138 μl(0.991 mmol) of triethylamine to give the title compound (272 mg, 96%).##STR83## TLC:methylene chloride/methanol/cone. ammonia (1000:50:1)R_(f) =0.73, FD-MS: (M+H)⁺ =516, 518, 520, IR:3420, 1625 cm⁻¹.

The starting compound for this is prepared as follows:

a) (2R*,4S*)-2-Benzyl-4-piperidine azide

15 g (38.3 mmol) of the mixture from Example 2e are reacted with 70 mlof trifluoroacetic acid in analogy to Example 38d. The title compound(7.15 g, 87%) is obtained as oil. TLC:methylene chloride/methanol/cone.ammonia (350:50:1) R_(f) =0.57, FD-MS:M⁺ =216.

b) (2R*,4S*)-2-Benzyl-1-(3,5-dichlorobenzoyl)-4-piperidine azide

6.62 g (34.7 mmol) of 3,5-dichlorobenzoic acid are reacted in analogy toExample 2a first with 3.78 ml (52.0 mmol) of thionyl chloride andsubsequently with 3.0 g (13.9 mmol) of (2R*,4S*)-2-benzyl-4-piperidineazide and 5.8 ml (41.6 mmol) of triethylamine to give the title compound(5.18 g, 96%). TLC:methylene chloride/methanol/cone. ammonia (2000:50:1)R_(f) =0.77, DCI-MS:(M+H)⁺ =389, 391.

c) (2R*,4S*)-2-Benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine

11.0 g (28.3 mmol) of(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidine azide arehydrogenated with 10% Pd/C in analogy to Example 2f. The title compound(8.76 g, 85%) is obtained as oil. TLC:methylene chloride/methanol/cone.ammonia (350:50:1) R_(f) =0.40, FD-MS:M⁺ =362, 364.

EXAMPLE 58(2R*,4S*)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-(3,5-dimethylbenzoyl)-4-piperidinamine

124 mg (0.825 mmol) of 3,5-dimethylbenzoic acid are reacted in analogyto Example 2a first with 2 ml (27 mmol) of thionyl chloride andsubsequently with 200 mg (0.550 mmol) of(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine and 138 μl(0.991 mmol) of triethylamine to give the product (200 mg, 73%).##STR84## TLC:methylene chloride/methanol/conc. ammonia (2000:50:1)R_(f) =0.61, FD-MS:(M+H)⁺ =494, 496; IR:3420, 1625 cm⁻¹

EXAMPLE 59(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylcarbonyl)-4-piperidinamine

200 mg (0.550 mmol) of(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reactedin analogy to Example 4a with 105 mg (0.660 mmol) ofquinoline-4-carboxylic acid, 168 mg (0.661 mmol) ofbis(2-oxo-3-oxazolidinyl)phosphinic chloride and 169 μl (1.21 mmol) oftriethylamine. The title compound ##STR85## is obtained (278 mg, 97%) asoil. TLC:methylene chloride/methanol/cone. ammonia (700:50:1) R_(f)=0.45, FD-MS:M⁺ =517, 519; IR:3395, 1755, 1620 cm⁻¹.

EXAMPLE 60(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(3-indolylcarbonyl)-4-piperidinamine

200 mg (0.550 mmol) of(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reactedin analogy to Example 4a with 106 mg (0.661 mmol) of indole-3-carboxylicacid, 168 mg (0.661 mmol) of bis(2-oxo-3-oxazolidinyl)phosphinicchloride and 169 μl (1.21 mmol) of triethylamine. The title compound##STR86## is obtained (92 mg, 33%) as oil. TLC:methylenechloride/methanol/cone. ammonia (350:50:1) R_(f) =0.61, FD-MS:M⁺ =505,507; IR:3450, 3260, 1770, 1635 cm⁻¹.

EXAMPLE 61(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(2-indolylcarbonyl)-4-piperidinamine

200 mg (0.550 mmol) of(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reactedin analogy to Example 4a with 106 mg (0.661 mmol) of indole-2-carboxylicacid, 168 mg (0.661 mmol) of bis(2-oxo-3-oxazolidinyl)phosphinicchloride and 169 μl (1.21 mmol) of triethylamine. The title compound##STR87## is obtained (89 mg, 32%) as white crystals with melting point254° C. TLC:methylene chloride/methanol/cone. ammonia (2000:50:1) R_(f)=0.56, FD-MS:M⁺ =505, 507; IR:3430, 3290, 1625 cm⁻¹.

EXAMPLE 62(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(5-methoxy-2-indolylcarbonyl)-4-piperidinamine

200 mg (0.550 mmol) of(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reactedin analogy to Example 4a with 126 mg (0.661 mmol) of5-methoxyindole-2-carboxylic acid, 168 mg (0.661 mmol) ofbis(2-oxo-3-oxazolidinyl)phosphinic chloride and 169 μl (1.21 mmol) oftriethylamine. The title compound ##STR88## is obtained (118 mg, 41%) aswhite crystals of melting point 251° C. TLC:methylenechloride/methanol/cone. ammonia (2000:50:1) R_(f) =0.81, FD-MS:M⁺ =535,537; IR:3440, 3280, 1625 cm⁻¹.

EXAMPLE 63(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(1-naphthoyl)-4-piperidinamine

150 mg (0.431 mmol) of(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reactedin analogy to Example 39a with 75 μl (0.495 mmol) of 1-naphthoylchloride and 81 μl (0.578 mmol) of triethylamine. The title compound##STR89## is obtained (208 mg, 97%) as oil. TLC:methylenechloride/methanol/conc. ammonia (1000:50:1) R_(f) =0.85, FD-MS:M⁺ =516,518; IR:3680, 3400, 1620 cm⁻¹.

EXAMPLE 64(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(phenylacetyl)-4-piperidinamine

200 mg (0.551 mmol) of(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reactedin analogy to Example 39a with 88 μl (0.661 mmol) of phenylacetylchloride and 108 μl (0.771 mmol) of triethylamine. The title compound##STR90## is obtained (127 mg, 48%) as white foam. TLC:methylenechloride/methanol/conc. ammonia (1000:50:1) R_(f) =0.56, FD-MS:M⁺ =480,482; IR:3660, 3405, 1665, 1630 cm⁻¹.

EXAMPLE 65(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(2-methoxybenzyl)-4-piperidinamine

200 mg (0.551 mmol) of(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reactedin analogy to Example 2g with 75 mg (0.551 mmol) of2-methoxybenzaldehyde and 90 mg magnesium sulfate in 2 ml of toluene andsubsequently reduced with 22 mg (0.584 mmol) of sodium borohydride in 2ml of methanol. The title compound ##STR91## is obtained (170 mg, 64%)as white foam. TLC:methylene chloride/methanol/cone. ammonia (700:50:1)R_(f) =0.66, FD-MS:M⁺ =482, 482. IR:1620 cm⁻¹.

EXAMPLE 66(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(3-(N-acetyl)indolylmethyl)-4-piperidinamine

200 mg (0.551 mmol) of(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reactedin analogy to Example 2g with 113 mg (0.606 mmol) ofN-acetylindole-3-carboxaldehyde and 90 mg of magnesium sulfate in 2 mlof toluene and subsequently reduced with 31 mg (0.826 mmol) of sodiumborohydride in 3 ml of methanol. The title compound ##STR92## isobtained (30 mg, 10%) as oil. TLC:methylene chloride/methanol/conc.ammonia (1000:50:1) R_(f) =0.57, FD-MS:M⁺ =533, 535. IR:1720, 1680, 1635cm⁻¹.

EXAMPLE 67(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(2-benzo[b]furanylmethyl)-4-piperidinamine

200 mg (0.551 mmol) of(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reactedin analogy to Example 2g with 97 mg (0.661 mmol) ofbenzofuran-2-carboxaldehyde and 90 mg of magnesium sulfate in 2 ml oftoluene and subsequently reduced with 22 mg (0.584 mmol) of sodiumborohydride in 2 ml of methanol. The title compound ##STR93## isobtained (150 mg, 55%) as oil. TLC:methylene chloride/methanol/cone.ammonia (2000:50:1) R_(f) =0.18, FD-MS:M⁺ =492, 494. IR:1630 cm⁻¹.

EXAMPLE 68(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-[(3-methylbenzo[b]thiophen-2-ylmethyl]-4-piperidinamine

200 mg (0.551 mmol) of(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reactedin analogy to Example 2g with 116 mg (0.661 mmol) of3-methylbenzo[b]thiophene-2-carboxaldehyde and 90 mg of magnesiumsulfate in 2 ml of toluene and subsequently reduced with 22 mg (0.584mmol) of sodium borohydride in 2 ml of methanol. The title compound##STR94## is obtained (75 mg, 25%) as white foam. TLC:methylenechloride/methanol/conc. ammonia (2000:50:1) R_(f) =0.38, FD-MS:M⁺ =522,524. IR:1630 cm⁻¹.

EXAMPLE 69(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(5-methoxyindol-3-yl-methyl)-4-piperidinamine

200 mg (0.551 mmol) of(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reactedin analogy to Example 2g with 116 mg (0.661 mmol) of5-methoxyindole-3-carboxaldehyde and 90 mg of magnesium sulfate in 2 mlof toluene and subsequently reduced with 22 mg (0.584 mmol) of sodiumborohydride in 2 ml of methanol. The title compound ##STR95## isobtained (98 mg, 34%) as white foam. TLC:methylenechloride/methanol/conc. ammonia (1000:50:1) R_(f) =0.42, FD-MS:M⁺ =521,523. IR:3460, 1630 cm⁻¹.

EXAMPLE 70(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(3-indolylmethyl)-4-piperidinamine

200 mg (0.551 mmol) of(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reactedin analogy to Example 2g with 80 mg (0.551 mmol) ofindole-3-carboxaldehyde and 90 mg of magnesium sulfate in 2 ml oftoluene and subsequently reduced with 22 mg (0.584 mmol) of sodiumborohydride in 2 ml of methanol. The title compound ##STR96## isobtained (75 mg, 28%) as while foam. TLC:methylenechloride/methanol/cone. ammonia (400:50:1) R_(f) =0.49, FD-MS:M⁺ =491,493. IR:3460, 1630 cm⁻¹ .

EXAMPLE 71(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-phenylcarbamoyl-4-piperidinamine

200 mg (0.551 mmol) of(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reactedwith 85 mg (0.716 mmol) of phenyl isocyanate in analogy to Example 16a.The title compound ##STR97## is obtained as white foam (160 mg, 60%).TLC:tolnene/ethyl acetate (1:1) R_(f) =0.40, FD-MS:M⁺ =481, 483;IR:1600-1690 cm⁻¹.

EXAMPLE 72(2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-diphenylmethyl-4-piperidinamine

A solution of 200 mg (0.551 mmol) of(2R*,45*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine and 110 mg(0.606 mmol) of benzophenone in 5 ml of toluene are kept at reflux for18 hours. The reaction mixture is then concentrated in a rotaryevaporator and dissolved in 3 ml of methanol, and 69 mg (1.10 mmol) ofsodium cyanoborohydride are added at RT. The reaction mixture isadjusted to pH=5 with 80 μl of acetic acid and stirred at RT for 68hours. The title compound ##STR98## is obtained as white foam (120 mg,41%). TLC:toluene/ethyl acetate (7:3) R_(f) =0.79, FD-MS:M⁺ =528, 530;IR:1630 cm⁻¹.

EXAMPLE 73(2R*,45*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(3,4-dihydro-2H-1-benzopyran-2-carbonyl)-4-piperidinamine

125 mg (0.606 mmol) of N,N'-dicyclohexylcarbodiimide are added to asolution of 108 mg (0.606 mmol) of3,4-dihydro-2H-1-benzopyran-2-carboxylic acid in 3 ml of tetrahydrofuranat 0° C., and the reaction mixture is stirred for one hour and 177 μl(1.27 mmol) of triethylamine and 200 mg (0.551 mmol) of(2R*,45*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are added.The mixture is allowed to warm to RT and is stirred at this temperaturefor 16 hours. It is concentrated in a rotary evaporator, the residue issuspended in methylene chloride/ether (1:1), and the white suspension isfiltered. After concentration in a rotary evaporator the reactionmixture is taken up in methylene chloride, washed twice with 10% citricacid, once with water, once with 2N sodium hydroxide solution and oncewith brine, dried over magnesium sulfate and evaporated in a rotaryevaporator. The yellow oil is chromatographed on silica gel withtoluene/ethyl acetate (7:3). The mixture of diastereomers of the titlecompound ##STR99## is obtained as white foam (69 mg, 24%).TLC:toluene/ethyl acetate (1:1) R_(f) =0.56, FD-MS:M⁺ =522, 524;IR:3410, 1675, 1630 cm⁻¹.

EXAMPLE 74(2R*,4S*)-2-benzyl-1-(4-methoxybenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine

0.175 g (0.321 mmol) of(2R*,4S*)-2-benzyl-1-(4-methoxybenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamineis reacted with 0.047 g (1.25 mmol) of sodium borohydride in analogy toExample 2. The title compound ##STR100## is obtained (0.100 g, 69%) aswhite foam. TLC:methylene chloride/methanol/conc. ammonia (1000:50:1)R_(f) =0.21, FD-MS:M⁺ =465; IR:1620 cm⁻¹.

The starting comopund for this is prepared as follows:

(2R*,4S*)-2-Benzyl-1-(4-methoxybenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine

200 mg (0.467 mmol) of(2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-1-piperidinamineare reacted in analogy to Example 4a with 85 mg (0.562 mmol) ofp-anissic acid, 143 mg (0.561 mmol) ofbis(2-oxo-3-oxazolidinyl)phosphinic chloride and 91 μl (0.655 mmol) oftriethylamine. The title compound (170 mg, 65%) is obtained as whitefoam. TLC:methylene chloride/methanol/cone. ammonia (1000:50:1) R_(f)=0.37, FD-MS:M⁺ =561.

EXAMPLE 75 The following can furthermore be prepared in an analogousmanner as in Examples 1 to 74:

(2R*,4S*)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-benzyl-N-carbamoyl-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(3-phenylpropyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(3-phenylpropyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(2-methoxybenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(2-methoxybenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2-methoxyphenyl)ethyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2-methoxyphenyl)ethyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2-methoxyphenyl)propyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2-methoxyphenyl)propyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(2-trifluoromethylbenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(2-trifluoromethylbenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2-trifluoromethylphenyl)ethyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2-trifluoromethylphenyl)ethyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2-trifluoromethylphenyl)propyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2-trifluoromethylphenyl)propyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(3-trifluoromethylbenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(3-trifluoromethylbenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(3-trifluoromethylphenyl)ethyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(3-trifluoromethylphenyl)ethyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(3-trifluoromethylphenyl)propyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(3-trifluoromethylphenyl)propyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(4-trifluoromethylbenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(4-trifluoromethylbenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(4-trifluoromethylphenyl)ethyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(4-trifluoromethylphenyl)ethyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(4-trifluoromethylphenyl)propyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(4-trifluoromethylphenyl)propyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(2,3-dimethoxybenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(2,3-dimethoxybenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2,3-dimethoxyphenyl)ethyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2,3-dimethoxyphenyl)ethyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2,3-dimethoxyphenyl)propyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2,3-dimethoxyphenyl)propyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(2,4-dimethoxybenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(2,4-dimethoxybenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2,4-dimethoxyphenyl)ethyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2,4-dimethoxyphenyl)ethyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2,4-dimethoxyphenyl)propyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2,4-dimethoxyphenyl)propyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(2,5-dimethoxybenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(2,5-dimethoxybenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2,5-dimethoxyphenyl)ethyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2,5-dimethoxyphenyl)ethyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2,5-dimethoxyphenyl)propyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2,5-dimethoxyphenyl)propyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(2,6-dimethoxybenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(2,6-dimethoxybenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2,6-dimethoxyphenyl)ethyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2,6-dimethoxyphenyl)ethyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2,6-dimethoxyphenyl)propyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2,6-dimethoxyphenyl)propyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(2,3-methylenedioxybenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(2,3-methylenedioxybenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2,3-methylenedioxyphenyl)ethyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2,3-methylenedioxyphenyl)ethyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2,3-methylenedioxyphenyl)propyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2,3-methylenedioxyphenyl)propyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(2,4-methylenedioxybenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(2,4-methylenedioxybenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2,4-methylenedioxyphenyl)ethyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2,4-methylenedioxyphenyl)ethyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2,4-methylenedioxyphenyl)propyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2,4-methylenedioxyphenyl)propyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(indol-2-ylmethyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(indol-2-ylmethyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(indol-3-ylmethyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(quinolin-2-ylmethyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(indol-3-ylmethyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(quinolin-3-ylmethyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(2-chlorobenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(2-chlorobenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2-chlorophenyl)ethyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2-chlorophenyl)ethyl]-4-piperidinamine:

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2-chlorophenyl)propyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2-chlorophenyl)propyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(3-chlorobenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(3-chlorobenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(3ochlorophenyl)ethyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(3-chlorophenyl)ethyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(3-chlorophenyl)propyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(3-chlorophenyl)propyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(4-chlorobenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(4-chlorobenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(4-chlorophenyl)ethyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(4-chlorophenyl)ethyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(4-chlorophenyl)propyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(4-chlorophenyl)propyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(4-methoxynaphth-1-ylmethyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(4-methoxynaphth-1-ylmethyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(3,4-ethylenedioxybenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(3,4-ethylenedioxybenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(indol-2-ylmethyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(indol-2-ylmethyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(indol-3-ylmethyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(indol-3-ylmethyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(quinolin-2-ylmethyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(quinolin-2-ylmethyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(quinolin-3-ylmethyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(quinolin-3-ylmethyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(2-chlorobenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(2-chlorobenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2-chlorophenyl)ethyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2-chlorophenyl)ethyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2-chlorophenyl)propyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2-chlorophenyl)propyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(3-chlorobenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(3-chlorobenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(3-chlorophenyl)ethyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(3-chlorophenyl)ethyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(3-chlorophenyl)propyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(3-chlorophenyl)propyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(4-chlorobenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(4-chlorobenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(4-chlorophenyl)ethyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(4-chlorophenyl)ethyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(4-chlorophenyl)propyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(4-chlorophenyl)propyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(4-methoxynaphth-1-ylmethyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(4-methoxynaphth-1-ylmethyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(3,4-ethylenedioxybenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(3,4-ethylenedioxybenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(indol-2-ylmethyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(indol-2-ylmethyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(indol-3-ylmethyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(indol-3-ylmethyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(quinolin-2-ylmethyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(quinolin-3-ylmethyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(quinolin-3-ylmethyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(2-chlorobenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(2-chlorobenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2-chlorophenyl)ethyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2-chlorophenyl)ethyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2-chlorophenyl)propyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2-chlorophenyl)propyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(3-chlorobenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(3-chlorobenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(3-chlorophenyl)ethyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(3-chlorophenyl)ethyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(3-chlorophenyl)propyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(3-chlorophenyl)propyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(4-chlorobenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(4-chlorobenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(4-chlorophenyl)ethyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(4-chlorophenyl)ethyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(4-chlorophenyl)propyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(4-chlorophenyl)propyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(4-methoxynaphth-1-ylmethyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(4-methoxynaphth-1-ylmethyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(3,4-ethylenedioxybenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethylbenzoyl)-N-(3,4-ethylenedioxybenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(indol-2-ylmethyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(indol-2-ylmethyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(indol-3-ylmethyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(indol-3-ylmethyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(quinolin-2-ylmethyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(quinolin-2-ylmethyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(quinolin-3-ylmethyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(quinolin-3-ylmethyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(2-chlorobenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(2-chlorobenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-[2-(2-chlorophenyl)ethyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-[2-(2-chlorophenyl)ethyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-[3-(2-chlorophenyl)propyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-[3-(2-chlorophenyl)propyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(3-chlorobenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(3-chlorobenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-[2-(3-chlorophenyl)ethyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-[2-(3-chlorophenyl)ethyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-[3-(3-chlorophenyl)propyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-[3-(3-chlorophenyl)propyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(4-chlorobenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(4-chlorobenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-[2-(4-chlorophenyl)ethyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-[2-(4-chlorophenyl)ethyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-[3-(4-chlorophenyl)propyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-[3-(4-chlorophenyl)propyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(4-methoxynaphth-1-ylmethyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(4-methoxynaphth-1-ylmethyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(3,4-ethylenedioxybenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(3,4-ethylenedioxybenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-(indol-2-ylmethyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-(indol-2-ylmethyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-(indol-3-ylmethyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-(indol-3-ylmethyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-(quinolin-2-ylmethyl)-4-piperidinamine:

(2S,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-(quinolin-2-ylmethyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-(quinolin-3-ylmethyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-(quinolin-3-ylmethyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-(2-chlorobenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-(2-chlorobenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-[2-(2-chlorophenyl)ethyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-[2-(2-chlorophenyl)ethyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-[3-(2-chlorophenyl)propyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-[3-(2-chlorophenyl)propyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-(3-chlorobenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-(3-chlorobenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-[2-(3-chlorophenyl)ethyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-[2-(3-chlorophenyl)ethyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-[3-(3-chlorophenyl)propyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-[3-(3-chlorophenyl)propyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-(4-chlorobenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-(4-chlorobenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-[2-(4-chlorophenyl)ethyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-[2-(4-chlorophenyl)ethyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-[3-(4-chlorophenyl)propyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-[3-(4-chlorophenyl)propyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-(4-methoxynaphth-1-ylmethyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-(4-methoxynaphth-1-ylmethyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-(3,4-ethylenedioxybenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dichlorobenzoyl)-N-(3,4-ethylenedioxybenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethoxybenzoyl)-N-(indol-2-ylmethyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethoxybenzoyl)-N-(indol-2-ylmethyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethoxybenzoyl)-N-(indol-3-ylmethyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethoxybenzoyl)-N-(indol-3-ylmethyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethoxybenzoyl)-N-(quinolin-2-ylmethyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethoxybenzoyl)-N-(quinolin-2-ylmethyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethoxybenzoyl)-N-(quinolin-3-ylmethyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethoxybenzoyl)-N-(quinolin-3-ylmethyl)-4-piperidinamine:

(2R,4S)-2-Benzyl-1-(3,5-dimethoxybenzoyl)-N-(2-chlorobenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethoxybenzoyl)-N-(2-chlorobenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethoxybenzoyl)-N-[2-(2-chlorophenyl)ethyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethoxybenzoyl)-N-[2-(2-chlorophenyl)ethyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethoxybenzoyl)-N-[3-(2-chlorophenyl)propyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethoxybenzoyl)-N-[3-(2-chlorophenyl)propyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethoxybenzoyl)-N-(3-chlorobenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethoxybenzoyl)-N-(3-chlorobenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethoxybenzoyl)-N-[2-(3-chlorophenyl)ethyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethoxybenzoyl)-N-[2-(3-chlorophenyl)ethyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethoxybenzoyl)-N-[3-(3-chlorophenyl)propyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethoxybenzoyl)-N-[3-(3-chlorophenyl)propyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethoxybenzoyl)-N-(4-chlorobenzyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethoxybenzoyl)-N-(4-chlorobenzyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethoxybenzoyl)-N-[2-(4-chlorophenyl)ethyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethoxybenzoyl)-N-[2-(4-chlorophenyl)ethyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethoxybenzoyl)-N-[3-(4-chlorophenyl)propyl]-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethoxybenzoyl)-N-[3-(4-chlorophenyl)propyl]-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethoxybenzoyl)-N-(4-methoxynaphth-1-ylmethyl)-4-piperidinamine;

(2S,4S)-2-Benzyl-1-(3,5-dimethoxybenzoyl)-N-(4-methoxynaphth-1-ylmethyl)-4-piperidinamine;

(2R,4S)-2-Benzyl-1-(3,5-dimethoxybenzoyl)-N-(3,4-ethylenedioxybenzyl)-4-piperidinamineand

(2S,4S)-2-Benzyl-1-(3,5-dimethoxybenzoyl)-N-(3,4-ethylenedioxybenzyl)-4-piperidinamine.

EXAMPLE 76 (2R,4S)- and(2R,4R)2-benzyl-1-(3,5-dimethylbenzoyl)-N-(4-quinolylmethyl)-4-piperidinaminedihydrochloride

A mixture of the hydrochlorides of the two diastereomeric titlecompounds is obtained in analogy to Example 1starting from 1.26 g (3.9mmol) of (2R,4R/S)-2-benzyl-1-(3,5-dimethylbenzoyl)-4-piperidinamine,obtained as mixture of about 70% of (2R,4R)- and about 30% of (2R,4S)-diastereomers by reduction with borane/dimethyl sulfide according toExample e1b, and using a total of 2.26 g (14.4 mmol) ofquinoline-4-carboxaldehyde. ##STR101## TLC:methylenechloride/methanol/conc. ammonia (90:9:1) Diastereomer A (2R,4R):R_(f)=0.5, MS:M⁺ =463 Diastereomer B (2R,4S):R_(f) =0.45, MS:M⁺ =463, meltingpoint 144°-145°, [α]_(D) =+25° (c=0.94 in ethanol)

These are treated, dissolved in ethyl acetate, with ethereal HClsolution, resulting in the dihydrochloride of the title compound.

TLC:methylene chloride/methanol/conc. ammonia (90:9:1) Diastereomer A(2R,4R):R_(f) =0.5, melting point 172°-174°, [α]_(D) =-55.7° (c=1,ethanol) Diastereomer B (2R,4S):R_(f) =0.45, melting point 174°-176°,[α]_(D) =+18° (c=1, ethanol)

EXAMPLE 77 (2S,4R) and(2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(2-phenethyl)-4-piperidinaminehydrochloride

The hydrochlorides of the two diastereomeric title compounds areobtained in analogy to Example 1 starting from 1.87 g (5.8 mmol) of(2S,4R/S)-2-benzyl-1-(3,5-dimethylbenzoyl)-4-piperidinamine, obtained asmixture of about 70% of (2S,4S)- and about 30% of (2S,4R)- diastereomersby reduction using borane/dimethyl sulfide according to Example e1b, andusing phenylacetaldehyde. TLC:methylene chloride/methanol (98:2)Diastereomer A (2S,4S):R_(f) =0.16, melting point 250°-251° C., [α]_(D)=+56.2° (c=0.980, methanol), MS:M⁺ =426 (free base). Diastereomer B(2S,4R):R_(f) =0.06, melting point 250° C. (decomposition), [α]_(D)=-29.7° (c=0.768, methanol), MS:M⁺ =426 (free base).

EXAMPLE 78(2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(3-quinolylmethyl)-4-piperidinamine

The title compound is obtained in the form of colourless crystals inanalogy to Example 1 starting from 511 mg (1.59 mmol) of(2R,4RS)-2-benzyl-1-(3,5-dimethylbenzoyl)-4-piperidinamine usingquinoline-3-carbaldehyde and by crystallisation from hexane/ethylacetate (1:1).

TLC:methylene chloride/methanol/cone. ammonia (90:9:1) R_(f) =0.5,melting point 91°-93° C., MS:M⁺ =463 (free base), [α]_(D) =+0.7°(c=1.09, methanol)

EXAMPLE 79(2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(2-quinolylmethyl)-4-piperidinaminedihydrochloride

The dihydrochlorides of the title compound are obtained in analogy toExample 1 starting from 541 mg (1.68 mmol) of(2R,4RS)-2-benzyl-1-(3,5-dimethylbenzoyl)-4-piperidinamine usingquinoline-2-carbaldehyde.

TLC:methylene chloride/methanol/cone. ammonia (90:9:1) R_(f) =0.5,decomposition point:from 110° C., MS:M⁺ =463 (free base), [α]_(D) =+4.8°(c=1.105, methanol)

EXAMPLE 80 (2R,4S)- and(2R,4R)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-benzyl-4-piperidinaminehydrochloride

The hydrochlorides of the two diastereomeric title compounds areobtained in analogy to Example 1 starting from 0.748 g (2.32 mmol) of(2R,4R/S)-2-benzyl-1-(3,5-dimethylbenzoyl)-4-piperidinamine, obtained asmixture of about 70% of (2R,4R)- and about 30% of (2R,4S)- diastereomersby reduction using borane/dimethyl sulfide according to Example e1b, andusing benzaldehyde.

TLC:methylene chloride/methanol/cone. ammonia (95:4.5:0.5) DiastereomerA (2R,4R):R_(f) =0.45, melting point 244°-246° C., [α]_(D) =-50.4°(c=0.979, chloroform), MS:M⁺ =412 (free base). Diastereomer B(2R,4S):R_(f) =0.33, amorphous. [α]_(D) =+7.9° (c=1.0, chloroform),MS:M⁺ =412 (free base).

EXAMPLE 81 (2S,4R)- and(2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-benzyl-4-piperidinaminehydrochloride

The hydrochlorides of the two diastereomeric title compounds areobtained in analogy to Example 1starting from 4.5 g (13.95 mmol) of(2S,4R/S)-2-benzyl-1-(3,5-dimethylbenzoyl)-4-piperidinamine, obtained asmixture of about 70% of (2S,4S)- and about 30% of (2S,4R)- diastereomersby reduction using borane/dimethyl sulfide according to Example e1b, andusing benzaldehyde.

TLC:methylene chloride/methanol/cone. ammonia (95:4.5:0.5) DiastereomerA (2S,4S):R_(f) =0.45, melting point 246°-247° C., [α]_(D) =+51.2°(c=0.672,chloroform), MS:M⁺ =412 (free base). Diastereomer B(2S,4R):R_(f) =0.33, amorphous. [α]_(D) =-7.7° (c=0.784, chloroform),MS:M⁺ =412 (free base).

EXAMPLE 82 (2R,4S)- and(2R,4R)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(4-pyridylmethyl)-4-piperidinaminedihydrochloride

The dihydrochlorides of the two diastereomeric title compounds areobtained in analog to Example 1 starting from 100 mg (0.279 mmol) of(2R,4R/S)-2-benzyl-1-(3,5-dimethylbenzoyl)-4-piperidinamine, obtained asmixture of about 70% of (2R,4R)- and about 30% of (2R,4S)- diastereomersby reducing using borane/dimethyl sulfide according to Example e1b, andusing pyridine-4-carbaldehyde.

TLC:methylene chloride/methanol/conc. ammonia (9°:9:1) Diastereomer A(2R,4R):R_(f) =0.68, from 142° C. decomposition, [α]_(D) =-57.3°(c=0.508, ethanol), MS:M⁺ =413 (free base). Diastereomer B (2R,4S):R_(f)=0.44, from 145° C. decomposition, [α]_(D) =+23.0° (c=0.300, ethanol),MS:M⁺ =413 (free base).

EXAMPLE 83 (2R,4S)- and(2R,4R)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(3-pyridylmethyl)-4-piperidinaminedihydrochloride

The dihydrochlorides of the two diastereomeric title comopunds areobtained in analogy to Example 1 starting from 100 mg (0.279 mmol) of(2R,4R/S)-2-benzyl-1-(3,5-dimethylbenzoyl)-4-piperidinamine, obtained asmixture of about 70% of (2R,4R)- and about 30% of (2R,4S)- diastereomersby reducing using borane/dimethyl sulfide according to Example e1b, andusing pyridine-3-carbaldehyde.

TLC:methylene chloride/methanol/cone. ammonia (90:9:1) Diastereomer A(2R,4R):R_(f) =0.68, from 105° C. decomposition, [α]_(D) =-52.6°(c=1.06, ethanol), MS:M⁺ =413 (free base). Diastereomer B (2R,4S):R_(f)=0.44, from 105° C. decomposition, [α]_(D) =+22.6° (c=1.03, ethanol),MS:M⁺ =413 (free base).

EXAMPLE 84 (2S,4R) and(2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine

The analogy to Example 1 starting from 12.1 g (37.5 mmol) of(2S,4RS)-2-benzyl-1-(3,5-dimethylbenzoyl)-4-piperidinamine, obtained asmixture of about 70% of (2S,4S)- and about 30% of (2S,4R)- diastereomersby reduction using borane/dimethyl sulfide according to Example e1b, andusing quinoline-4-carbaldehyde.

TLC:methylene chloride/methanol/cone. ammonia (90:9:1) Diastereomer A(2S,4R):R_(f) =0.59, melting point 144°-145° C. (free base) [α]_(D)=-25.1° (c=1.0, ethanol), MS:M⁺ =463 (free base)

EXAMPLE 85(2R*,4S*,1'R*)-N-Benzyl-1-(3,5-dimethylbenzoyl)-2-(1'-hydroxy-1'-benzyl)-4-piperidin-amine(diastereomer A) and(2R*,4R*,1'R*)-N-benzyl-1-(3,5-dimethylbenzoyl)-2-(1'-hydroxy-1'-phenyl-methyl)-4-piperidinamine(diastereomer B) ##STR102##

A solution of 400 mg (1.18 mmol) of(2R*,1'R*-1-(3,5-dimethylbenzoyl)-2-(1'-hydroxy-1'-phenyl-methyl)-4-piperidoneand 139 mg (1.3 mmol) benzylamine in toluene/hexane is heated to refluxwith azeotropic removal of water for 18 hours. The reaction mixture isconcentrated under reduced pressure, and the remaining oil is taken offin methanol and, at 0° to 5°, 111 mg of sodium cyanoborohydride (85% inmineral oil) are added and stirred at 25° for 4 hours. The solvent isstripped off under reduced pressure, and the crude product is taken upin a mixture of ethyl acetate and 10% strength sodium carbonatesolution. The organic phase is separated off, dried over sodium sulfateand evaporated under reduced pressure. Chromatography on silica gel withethyl acetate as mobile phase yields the title compounds; TLC (ethylacetate): Diastereomer A:R_(f) =0.28; melting point 159°-160°Diastereomer B:R_(f) =0.09; melting point 190°-192°.

The starting material can be prepared as follows:

a) 1-tert-Butoxycarbonyl-4-piperidone ethylene ketal

26.1 g of di-tertiary-butyl dicarbonate dissolved in 20 ml of tolueneare slowly added to a stirred solution of 14.3 g of 4-piperidoneethylene ketal in 100 ml of toluene at 0° to 5°. The mixture is left tostir at room temperature for 2 hours and then evaporated under reducedpressure and distilled under reduced pressure. 22.2 g of the titlecompound are obtained, boiling point 83°-85° (0.2 Torr). TLC (ethylacetate/hexane; 1:3):R_(f) =0.20.

b)(2R*,1'R*)-1-tert-Butoxycarbonyl-2-(1'-hydroxy-1'-phenyl-methyl)4-piperidoneethylene ketal (diastereomer A) and(2R*,1'S*)-1-tert-butoxycarbonyl-2-(1'-hydroxy-1'-phenyl-methyl)4-piperidoneethylene ketal (diastereomer B)

24.3 g (100 mmol) of 1-tert-butoxycarbonyl-4-piperidone ethylene ketaland 32.8 ml of tetramethylethylenediamine are dissolved in 100 ml ofdiethyl ether and cooled to -70°, and 87.5 ml (120 mmol) of a solutionof secondary butyllithium (1.4 molar solution in cyclohexane/isopentane)are slowly added. The mixture is left to stir at -70° for 4 hours andthen 12.72 g (120 mmol) of benzaldehyde are added all at once and themixture is allowed to warm to 0°. Saturated ammonium chloride solutionis added to the reaction mixture which is then extracted by shaking withethyl acetate. The organic phase is separated off, washed with saturatedsodium chloride solution, dried over sodium sulfate and evaporated underreduced pressure. Chromatography on silica gel with ethyl acetate asmobile phase yields 12.2 g of diastereomer A and 21.6 g of diastereomerB of the title compound. TLC (ethyl acetate/hexane; 1:1): Diastereomer A(2R*,1'R*):R_(f) =0.43, melting point 133°-134° Diastereomer B(2R*,1'S*):R_(f) =0.34, melting point 114°-116°

c) 2-(1'-Hydroxy-1'-phenyl-methyl)-4-piperidone

A suspension of 2.6 g (7.44 mmol) of(2R*,1'R*)-1-tert-butoxycarbonyl-2-(1'-hydroxy-1'-phenyl-methyl)-4-piperidoneethylene ketal in 30 ml of 6N hydrochloric acid is heated at 60° for 1hour and then cooled, neutralised with sodium carbonate and extracted byshaking with ethyl acetate. The organic phase is dried over sodiumsulfate and evaporated under reduced pressure. The title compound ofm.p. 124°-126° and R_(f) =0.26 (methylenechlorid/methanol/25% aquousammonia, 90:9.5:0.5) is thus obtained.

d)(2R*,1'R*)-1-(3,5-Dimethylbenzoyl)-2-(1'-hydroxy-1'-phenyl-methyl)-4-piperidone##STR103##

The crude 2-(1'-hydroxy-1'-phenyl-methyl)-4-piperidone obtained asdescribed under c) hereinbefore is taken up in a mixture of 20 ml ofdichloromethane and 20 ml of saturated sodium bicarbonate solution,cooled to 0°-5° with stirring and, over the course of 1.5 hours, 1.5 g(8.9 mmol) of 3,5-dimethylbenzoyl chloride are added dropwise. Themixture is left to stir for 1 hour, diluted with ethyl acetate, washedsuccessively with 1N HCl and saturated sodium chloride solution, driedover sodium sulfate and evaporated to dryness under reduced pressure.The title compound can be purified by chromatography on silica gel withethyl acetate/hexane (1:1) as mobile phase yields 1.71 g of the titlecompound. TLC (ethyl acetate/hexane; 1:1):R_(f) =0.19, FD-MS:M+=338.

In an analogous manner as described hereinbefore under b), c) and d),also the follwing compounds can be prepared:

(2R*,1'R*)-1-(3,5-bistrifluoromethylbenzoyl)-2-{1'-hydroxy-1'-(4-chlorophenyl)-methyl}-4-piperidone, TLC (ethyl acetate/hexane;1:1):R_(f) =0.35; FD-MS:479, 481;

(2R*,1'R*)-1-(3,5-dimethylbenzoyl)-2-{1'-hydroxy-1'-(3,4-dichlorophenyl)methyl}-4-piperidone,TLC(ethyl acetate/hexan; 1:1):R_(f) =0.16, m.p. 222°-223°;

(2R*,1'S*)-1-(3,5-bistrifluoromethylbenzoyl)-2-{1'-hydroxy-1'-(4-chlorophenyl)-methyl}-4-piperidone;

(2R*,1'R*)-1-(3,5-bistrifluormethylbenzoyl)-2-{1'-hydroxy-1'-(3,4-dichlorophenyl)-methyl}-4-piperidone;

(2R*,1'R*)-1-(3,5-dimethylbenzoyl)-2-{1'-hydroxy-1'-(4-methoxyphenyl)methyl}-4-piperidone;

(2R*,1'S*)-1-(3,5-dimethylbenzoyl)-2-{1'-hydroxy-1'-(4-methoxyphenyl)methyl}-4-piperidone;

(2R*,1'R*)-1-(3,5-dimethylbenzoyl)-2-{1'-hydroxy-1'-(3-methoxyphenyl)methyl}-4-piperidone;

(2R*,1'S*)-1-(3,5-dDimethylbenzoyl)-2-{1'-hydroxy-1'-(3-methoxyphenyl)methyl}-4-piperidone;

(2R*,1'R*)-1-(3,5-dimethylbenzoyl)-2-{1'-hydroxy-1'-(4-trifluormethylphenyl)-methyl}-4-piperidone;

(2R*,1'S*)-1-(3,5-dimethylbenzoyl)-2-{1'-hydroxy-1'-(4-trifluoromethylphenyl)-methyl}-4-piperidone;

(2R*,1'R*)-1-(3,5-dimethylbenzoyl)-2-{1'-hydroxy-1'-(4-chloro-3-trifluoromethyl-phenyl)methyl}-4-piperidoneand

(2R*,1'S*)-1-(3,5-dDimethylbenzoyl)-2-{1'-hydroxy-1'-(4-chloro-3-trifluoromethyl-phenyl)-methyl}-4-piperidone.

EXAMPLE 86(2R*,4S*,1'R*)-2-(1'-Hydroxy-1'-phenyl-methyl)1-(3,5-dimethylbenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine(diastereomer A) and(2R*,4R*,1'R*)-1-(3,5-dimethylbenzoyl)-2-(1'-hydroxy-1'-phenyl-methyl)-N-(4-quinolylmethyl)-4-piperidinamine(diastereomer B) ##STR104##

The title compound can be prepared in an analogous manner as describedin Example 85 starting from 4-quinolinemethylamine. It is fractionatedinto the diastereomers and be purified by column chromatography onsilica gel with ethyl acetate and ethyl acetate/methanol (50:1) asmobile phase. TLC (ethyl acetate): Diastereomer A (2R*,4S*,1'R*):yield180 mg; R_(f) =0.08, FD-MS:M+=479 Diastereomer B (2R*,4R*,1'R*):yield 35mg; R_(f) =0.01, FD-MS:M+=479

EXAMPLE 87(2R*,4S*,1'S*)-1-(3,5-Dimethylbenzoyl)-2-(1'-hydroxy-1'-phenyl-methyl)-N-(4-quinolylmethyl)4-piperidinamine(diastereomer A) and(2R*,4R*,1'S*)-1-(3,5-dimethyl-benzoyl)-2-(1'-hydroxy-1'-phenyl-methyl)-N-(4-quinolylmethyl)-4-piperidinamine(diastereomer B) ##STR105##

The title compound can be prepared in an analogous manner as describedin Example 85 starting from 420 mg (1.24 mmol) of(2R*,1'S*)-1-(3,5-dimethylbenzoyl)-2-(1'-hydroxy-1'-phenyl-methyl)-4-quinolylmethylamine.It is fractionated into the diastereomers and be purified by columnchromatography on silica gel with ethyl acetate anddichloromethane/methanol/35% strength ammonia solution (95:4.5:0.5) asmobile phase. TLC (ethyl acetate): Diastereomer A (2R*,4S*,1'S*), yield250 mg:R_(f) =0.08, FD-MS:M+=479 Diastereomer B (2R*,4R*,1'S*), yield170 mg:R_(f) =0.01, FD-MS:M+=479

The starting material can be prepared, for example, as follows:

a)(2R*,1'S*)-1-(3,5-Dimethylbenzoyl)-2-(1'-hydroxy-1'-phenyl-methyl)-4-piperidone

The title compound is prepared in an analogous manner as described inExample 1c from 860 mg (2.46 mmol) of(2R*,1'S*)-1-tert-butoxycarbonyl-2-(1'-hydroxy-1'-phenyl-methyl)-4-piperidonethylene ketal (Example 1b) and be prepared by column chromatography onsilica gel with ethyl acetate/hexane (2:3) as mobile phase. Yield 400mg; TLC (ethyl acetate/hexane; 1:1):R_(f) =0.24; FD-MS:M+=337.

EXAMPLE 88(2R*,4S*,1'R*)-2-{1'-Hydroxy-1'-(4-chlorophenyl)methyl}-1-(3,5-dimethylbenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine(diastereomer A) and(2R*,4R*,1'R*)-1-(3,5-dimethylbenzoyl)-2-{1'-hydroxy-1'-(4-chlorophenyl)methyl}-N-(4-quinolylmethyl)-4-piperidinamine(diastereomer B) ##STR106##

The title compound can be prepared in an analogous manner as describedin Example 1 from 310 mg (0.833 mmol) of(2R*,1'R*)-1-(3,5-dimethylbenzoyl)2-{1'-hydroxy-1'-(4-chlorophenyl)methyl}4-piperidoneand 145 mg (0.92 mmol) 4-quinolylmethylamine and be fractionated andpurified by column chromatography on silica gel with ethylacetate/isopropanol (95:5-90:10) as mobile phase. Diastereomer A:yield225 mg. Diastereomer B:yield 80 mg. TLC (dichloromethane/methanol/25%strength ammonia solution (90:10:0.5) Diastereomer A(2R*,4S*,1'R*):R_(f) =0.47, FD-MS:(M+1)+=514 Diastereomer B(2R*,4R*,1'R*):R_(f) =0.35, FD-MS:M+=513

The starting material can be prepared, for example, as follows:

a)(2R*,1'R*)-1-tert-Butoxycarbonyl-2-{1'-hydroxy-1'-(4-chlorophenyl)methyl}-4-piperidoneethylene ketal (diastereomer A) and(2R*,1'S*)-1-tert-Butoxycarbonyl-2-{1'-hydroxy-1'-(4-chlorophenyl)methyl}-4-piperidoneethylene ketal (diastereomer B)

The title compound can be prepared in an analogous manner as describedin Example 1b starting from 4-chlorobenzaldehyde, fractionated andpurified by column chromatography on silica gel with ethylacetate/hexane (1:3) as mobile phase, and be crystallised from ethylacetate/hexane. TLC (ethyl acetate/hexane; 1:1):

Diastereomer A (2R*,1'R*):R_(f) =0.44, melting point 129°-130°Diastereomer B (2R*,1'S*):R_(f) =0.35, melting point 160°-161°

b)(2R*,1'R*)-1-(3;5-Dimethylbenzoyl)-2-{1'-hydroxy-1'(4-chlorophenyl)methyl}-4-piperidone

The title compound can be prepared in an analogous manner as describedin Example 1c and crystallises from ethyl acetate. Melting point222°-225°; TLC (ethyl acetate/hexane; 1.1):R_(f) =0.17

EXAMPLE 89(2R*,4S*,1'S*)-1-(3,5-Dimethylbenzoyl)-2-{1'-hydroxy-1'-(4-chlorophenyl)-methyl}-N-(4-quinolylmethyl)-4-piperidinamine(diastereomer A) and(2R*,4R*,1'S*)-1-(3,5-dimethylbenzoyl)-2-{1'-hydroxy-1'-(4-Chlorophenyl)-methyl}-N-(4-quinolylmethyl)-4-piperidinamine(diastereomer B) ##STR107##

The title compound can be prepared in an analogous manner as describedin Example 1 starting from(2R*,1'S*)-1-(3,5-dimethylbenzoyl)-2-{1'-hydroxy-1'-(4-chlorophenyl)methyl}-4-piperidoneas starting material and be fractionated and purified by columnchromatography on silica gel with dichloromethane/methanol/25% strengthammonia solution (95:4.5:0.5) as mobile phase. TLC (acetic acid):

Diastereomer A (2R*,4S*,1'S*):R_(f) =0.24, FD-MS:M+=514 Diastereomer B(2R*,4R*,1'S*):R_(f) =0.06, FD-MS:M+=514

The starting material can be prepared, for example, as follows:

a)(2R*,1'S*)1-(3,5-Dimethylbenzoyl)-2-{1'-hydroxy-1'-(4-chlorophenyl)methyl}-4-piperidone

The title compound is prepared in an analogous manner as described inExample 1c starting from(2R*,1'S*)-1-tert-butoxycarbonyl-2-{1'-hydroxy-1'-(4-chlorophenyl)methyl}-4-piperidoneethylene ketal (Example 4a, diastereomer B). Melting point 195°-197°;TLC (ethyl acetate/hexane; 1:1):R_(f) =0.26

EXAMPLE 90(2R*,4S*,1'S*)-1-(3,5-Dimethylbenzoyl)-2-{1'-hydroxy-1'-(3,4-dichlorophenyl)-methyl}-N-(4-quinolylmethyl)-4-piperidinamine(diastereomer A) and(2R*,4R*,1'S*)-1-(3,5-dimethylbenzoyl)-2-{1'-hydroxy-1'-(3,4-dichlorophenyl)-methyl}-N-(4-quinolylmethyl)-4-piperidinamine(diastereomer B) ##STR108##

The title compound is prepared in an analogous manner as described inExample 1 starting from(2R*,1'S*)-1-(3,5-dimethylbenzoyl)-2-{1'-hydroxy-1'-(3,4-dichlorophenyl)methyl}-4-piperidoneand fractionated by column chromatography on silica gel withdichloromethane/methanol/25% strength ammonia solution (93:6.5:0.5) asmobile phase. TLC (dichloromethane/methanol/25% strength ammoniasolution; 90:9.5:0.5):

Diastereomer A (2R*,4S*,1'S*):R_(f) =0.38; melting point 138°-140°Diastereomer B (2R*,4R*,1'S*):R_(f) =0.22; melting point 188°-190°

The starting material can be prepared, for example, as follows.

a)(2R*,1'R*)-1-tert-Butoxycarbonyl-2-{1'-hydroxy-1'-(3,4-dichlorophenyl)methyl}-4-piperidoneethylene ketal (diastereomer A) and(2R*,1'S*)-1-tert-butoxycarbonyl-2-{1'-hydroxy-1'-(3,4-dichlorophenyl)methyl}-4-piperidoneethylene ketal (diastereomer B)

The title compound is obtained in an analogous manner as described inExample 1b starting from 3,4-dichlorobenzaldehyde in place ofbenzaldehyde. The diastereomers are fractionated by columnchromatography on silica gel with ethyl acetate/hexane (1:3) as mobilephase and crystallised from ethyl acetate/hexane. TLC (ethylacetate/hexane; 1:1):

Diastereomer A (2R*,1'R*):R_(f) =0.57, IR spectrum (CH2Cl2):3700-3300,1680 cm⁻¹ Diastereomer B (2R*,1'S*):R_(f) =0.48, melting point 160°-162°

b)(2R*,1'S*)-1-(3,5-Dimethylbenzoyl)-2-{1'-hydroxy-1'-(3,4-dichlorophenyl)-methyl}-4-piperidone

The title compound is prepared in an analogous manner as described inExample 1c from(2R*,1'S*)-1-tert-butoxycarbonyl-2-{1'-hydroxy-1'-(3,4-dichlorophenyl)methyl}-4-piperidoneethylene ketal and crystallised from ethyl acetate/hexane; melting point152°-152.5°; TLC (ethyl acetate/hexane; 1:1), R_(f) =0.24

EXAMPLE 91(2R*,4S*)-N-Benzyl-1-(3,5-dimethylbenzoyl)-2-benzoyl-4-piperidinamine

A solution of 30 mg of(2R*,4R*,1'R*)-N-benzyl-N-trifluoroacetyl-1-(3,5-dimethyl-benzoyl)-2-benzoyl-4-piperidinaminein 5 ml of methanol and 1 ml of 5N sodium hydroxide solution is heatedat 60° for 10 minutes. It is allowed to cool to room temperature,diluted with 10% strength aqueous sodium bicarbonate solution andextracted by shaking twice with dichloromethane. The organic phases arecombined, dried over sodium sulfate and evaporated to dryness underreduced pressure. The title compound of the formula ##STR109## isobtained by column chromatography on silica gel with ethyl acetate asmobile phase. TLC (ethyl acetate):R_(f) =0.17; IR spectrum(CH2Cl2):1685, 1625, 1500 cm⁻¹.

The starting material can be obtained, for example, as follows:

a)(2R*,4R*,1'R*)-N-Benzyl-N-trifluoroacetyl-1-(3,5-dimethylbenzoyl)-2-benzoyl-4-piperidinamine

0.167 ml of trifluoroacetic anhydride is added to a solution of 80 mg(0.19 mmol) of(2R*,4R*,1'R*)-N-benzyl-1-(3,5-dimethylbenzoyl)-2-(1'-hydroxy-1'-phenyl-methyl)-4-piperidinamine(Example 1, diastereomer B) in 1 ml pyridine at 0°, and the mixture isstirred at 0° for 2 hours. The reaction mixture is diluted with diethylether and water and separated into the phases. The organic phase iswashed with 4N hydrochloric acid and saturated sodium chloride solution,dried over sodium sulfate and evaporated to dryness under reducedpressure. In order to remove doubly trifluoroacetylated by-products, thecrude product is heated in 3 ml of ethanol and 0.5 ml of triethylamineat 55° and again evaporated under reduced pressure. The residue is takenup in 3 ml of dichloromethane containing 3 Å molecular sieves, and 5 mgof tetrapropylammonium perruthenate and 100 mg of morpholine N-oxide areadded. The mixture is left to stir for 16 hours, filtered, diluted withdichloromethane, washed successively with sodium bisulfate solution,saturated sodium chloride solution and 5% strength copper sulfatesolution, dried over sodium sulfate, evaporated under reduced pressureand crystallised with diethyl ether/hexane; melting point 138°-139°; TLC(ethyl acetate/hexane; 1:1):R_(f) =0.71.

EXAMPLE 92(2R*,4S*)-2-(4-Chlorobenzyl)-1-(3,5-dimethylbenzoyl)-N-(4-quinolinylmethyl)-4-piperidinamine

A mixture of 550 mg (1.54 mmol) of(2R*,4S*)-2-(4-chlorobenzyl)-1-(3,5-dimethyl-benzoyl)-4-piperidinamineand 242 mg(1.54 mmol) of 4-quinolinecarboxaldehyde are dissolved in 30ml of toluene and evaporated to dryness under reduced pressure. This isrepeated twice more. The residue is taken up in 10 ml of ethanol, 70 mg(1.85 mmol) of sodium boranate are added and the mixture is stirred at25° for 3 hours. It is acidified with 1N hydrochloric acid and left tostir for 1 hour. The reaction mixture is poured into saturated aqueoussodium carbonate solution and extracted with ethyl acetate. The organicphase is washed with saturated sodium chloride solution, dried oversodium sulfate and evaporated to dryness under reduced pressure. Thecrude product is recrystallised twice from ethyl acetate and yields 320mg of the title compound of the formula ##STR110## in the form of whitecrystals; melting point 148°-9°; MS:M+497.

The starting materials can be prepared, for example, as:

a) N-5-(4-Chlorophenyl)pent-1-en-4-yl-3.5-dimethylbenzamide

4.3 g (25.6 mmol) of 3,5-dimethylbenzoyl chloride are added over thecourse of 2 hours to a stirred solution of 5.0 g (25.6 mmol) of2-{1-(4-chlorophenyl)}pent-4-enylamine and 5.33 ml (38.4 mol) oftriethylamine in 100 ml of dichloromethane at 0°. The reaction mixtureis stirred for a further 1 hour, 1N hydrochloric acid is added, and themixture is extracted with dichloromethane. The organic phase is washedwith saturated sodium chloride solution until neutral, dried over sodiumsulfate and evaporated under reduced pressure. The crude product iscrystallised from ethyl acetate/hexane and yields 7.36 g (88%) of whitecrystals; melting point 116°-118°; TLC (hexane/ethyl acetate; 3:1):R_(f) =0.37

b)N-{5-(4-Chlorophenyl)pent-1-en-4-yl}-N-ethoxymethyl-3,5-dimethylbenzamide

2.36 ml (25.2 mmol) of chloromethyl ethyl ether are added in smallportions over the course of 2 hours to a vigorously stirred solution of5.5 g (16.8 mmol) ofN-{5-(4-chlorophenyl)pent-1-en-4-yl}-3.5-dimethylbenzamide and 100 mg ofbenzyltributylammonium chloride in 15 ml of 50% strength aqueous sodiumhydroxide solution and 15 ml of dichloromethane at 0°-5°. The organicphase is taken up in dichloromethane and water, the organic phase isseparated off, dried over sodium sulfate and evaporated to dryness underreduced pressure. The oily residue is purified by chromatography onsilica gel with ethyl acetate/hexane (1:4) as mobile phase; TLC (ethylacetate/hexane; 1:3):R_(f) =0.50; 1H-NMR (300 MHz, CDCl3):mixture ofrotamers, δ=7.31-7.18 (m, 4 H), 7.04-6.85 (m, 2.6 H), 6.42 (hr. s, 0.4H), 5.92-5.60 (m, 1 H), 5.20-5.02 (m, 2 H), 4.54-4.24 (m, 2 H),3.96-3.67 (m, 1 H), 3.25-2.40 (m, 6 H), 2.28 (s, ca 5 H), 2.24 (s, ca 1H), 1.34-1.21(m, ca 0.5 H), 1.08 (t, J=7, ca 2.5 H).

c)(2R*,4S*)-2-(4-Chlorobenzyl)-1-(3,5-dimethylbenzoyl)-N-acetyl-4-piperidinamine

0.61 ml of tin tetrachloride and 0.24 ml of acetic anhydride are addedsuccessively to a solution of 1.0 g ofN-{5-(4-chlorophenyl)pent-1-en-4-yl}-N-ethoxymethyl-3,5-dimethylbenzamidein acetonitrile cooled to -20°. The reaction mixture is then stirred at-20° for 2 hours and at 25° for 1 hour, poured into saturated aqueoussodium bicarbonate solution and extracted with ethyl acetate. Theorganic phase is separated off, dried over sodium sulfate and evaporatedto dryness under reduced pressure. The crude title compound (orange oil)is purified by chromatography on silica gel withdichloromethane/methanol/25% strength ammonia solution (95:5:0.1) asmobile phase. TLC (dichloromethane/methanol/25% strength ammoniasolution; 90:10:0.1):R_(f) =0.45; FD-MS:M+=398

d) (2R*,4S*)-2-(4-Chlorobenzyl)-1-(3,5-dimethylbenzoyl)-4-piperidinamine

A suspension of 730 mg(1.83 mmol) of(2R*,4S*)-2-(4-chlorobenzyl)-1-(3,5-dimethyl-benzoyl)-N-acetyl-4-piperidinaminein 6N hydrochloric acid is heated at 100° for 16 hours, during which thestarting material dissolves. The reaction mixture is basified with 10%strength aqueous sodium carbonate solution and extracted with ethylacetate. The combined organic phases are dried over sodium sulfate andevaporated to dryness under reduced pressure. The crude title compoundis purified by chromatography on silica geI withdichloromethane/methanol/25% strength ammonia solution (90:10:0.1) asmobile phase and is obtained as almost colourless resin. TLC(dichloromethane/methanol/25% strength ammonia solution;90:10:0.1):R_(f) =0.26; FD-MS:(M+I)+=357

EXAMPLE 93(2R*,4S*)-2-(3,4-Dichlorobenzyl)-1-(3,5-dimethylbenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine

The title compound of the formula ##STR111## can be prepared in ananalogous manner as in Example 8 starting from(2R*,4S*)-2-(3,4-dichlorobenzyl)-1-(3,5-dimethylbenzoyl)-4-piperidinamineas starting material:melting point 121°-124°; TLC(dichloromethane/methanol/25% strength ammonia solution;90:9.5:0.5):R_(f) =0.30; FD-MS:M+=531/533

The starting material can be prepared as follows:

a) N-{5-(3,4-Dichlorophenyl)pent-1-ene-4-yl}-3,5-dimethylbenzamide

The title compound is obtained in 93% yield in an analogous manner asdescribed in Example 8a; melting point 155°-157°; IR spectrum(KBr):3230, 1625, 1595 cm-1; TLC (hexane/ethyl acetate; 2:1):R_(f) =0.46

b)N-{5-(3,4-Dichlorophenyl)pent-1-ene-4-yl}-N-ethoxymethyl-3,5-dimethylbenzamide

The title compound is obtained in an analogous manner as described inExample 8b; IR spectrum (film):1640, 1600 cm-1;) TLC (hexane/ethylacetate; 2:1):R_(f) =0.58

c)(2R*,4S*)-N-Acetyl-2-(3,4-dichlorobenzyl)-1-(3,5-dimethylbenzoyl)-4-piperidinamine

The title compound is obtained in an analogous manner as described inExample 8c; IR spectrum (KBr):3260, 1655, 1605, 1595, 1540 cm-1(KBr);TLC (dichloromethane/methanol; 10:1); R_(f) =0.32

d)(2R*,4S*)-2-(3,4-Dichlorobenzyl)-1-(3,5-dimethylbenzoyl)-4-piperidinamine

The title compound is obtained in an analogous manner as described inExample 8d; TLC (dichloromethane/methanol/25% strength ammonia solution;300:25:3):R_(f) 0.46

EXAMPLE 94(2R*,4S*)-1-(3,5-Dimethylbenzoyl)-2-phenyl-N-(4-quinolylmethyl)-4-piperidinamine

A suspension of 211 mg (0.60 mmol) of(2R*,4S*)-N-acetyl-1-(3,5-dimethylbenzoyl)-2-phenyl-4-piperidinamine in8 ml of 6N hydrochloric acid is heated at 100° under inert gas for 16hours, during which the starting material dissolves completely. Themixture is allowed to cool to room temperature, and is neutralised withsodium carbonate solution and extracted with ethyl acetate. Columnchromatography on silica gel with dichloromethane/methanol (95:5 to90:10) as mobile phase yields 135 mg of amine which, without furtherpurification, is reacted further with 60 mg (0.38 mmol) ofquinoline-4-carboxaldehyde in toluene with azeotropic removal of water.An oil remains after the solvent has been snipped off. This oil is takenup in ethanol and, at 0°, 14 mg (0.38 mmol) of sodium borohydride areadded. After 1.5 hours, the reaction mixture is treated with 1Nhydrochloric acid, stirred at 25° for 1hour and finally neutralised with10% strength aqueous sodium carbonate solution. It is extracted byshaking with ethyl acetate, and the organic phase is separated off,dried over sodium sulfate and evaporated to dryness under reducedpressure. The title compound of the formula ##STR112## is isolated bycolumn chromatography on silica gel with dichloromethane/isopropanol(9:1) as mobile phase; TLC (dichloromethane/isopropanol; 9:1):R_(f)=0.51; FD -MS:M+=449

The starting material can be prepared as follows:

a) (2R*,4S*)-N-Acetyl-1-benzyloxycarbonyl-2-phenyl-4-piperidinamine

1.41 ml (12.0 mmol) of tin tetrachloride are added to a solution of 2.03g (9.90 mmol) of N-but-3-en-1-yl-O-benzylcarboxamide and 1.14 g (10.7mmol) of benzaldehyde in 1 ml (810.6 mmol) of acetic anhydride and 20 mlof acetonitrile at -20°. The mixture is kept at -20 for 16 hours, thentreated with 10% strength aqueous sodium bicarbonate solution andextracted with ethyl acetate. The organic phase is dried over sodiumsulfate and evaporated to dryness under reduced pressure. The crudetitle compound is crystallised from ethyl acetate/hexane; melting point139°-140°; CI-MS:(M+H)+=353, (M+NH4)+=370.

b) (2R*,4S*)-N-Acetyl-1-(3,5-dimethylbenzoyl)-2-phenyl-4-piperidinamine

A solution of 496 mg (1.41 mmol) of(2R*,4S*)-N-acetyl-1-benzyloxycarbonyl-2-phenyl-4-piperidinamine in 30ml of ethanol and 8 ml of 1N hydrochloric acid is mixed with 50 mg of10% Pd/C catalyst and stirred under a hydrogen atmosphere until no morehydrogen is taken up. The catalyst is removed by filtration throughdiatomaceous earth, and the filtrate is evaporated to dryness underreduced pressure. The residue is taken up in 5 ml of dichloromethane and5 ml of 10% strength aqueous sodium bicarbonate solution and, whilestirring at 0°, 285 mg (1.69 mmol) of 3,5-dimethylbenzoyl chloride areadded slowly over the course of 1 hour. The reaction mixture isextracted with dichloromethane. The organic phase is separated off,dried over sodium sulfate and evaporated to dryness under reducedpressure. The title compound crystallises from ethyl acetate; meltingpoint 201°-203°; CI-MS:(M+H)+=351.

EXAMPLE 95(2R*,4S*)-1-(3,5-Dichlorobenzoyl)-2-phenyl-N-(4-quinolinmmthyl)-4-piperidinamine

The title compound of the formula ##STR113## can be obtained in ananalogous manner as described in Example 10; TLC(dichloromethane/methanol/25% strength ammonia solution;90:9.5:0:5):R_(f) =0.46; FD-MS:M+=489.

The starting material can be prepared as follows:

a) (2R*,4S*)-N-Acetyl-1-(3,5-dichlorobenzoyl)-2-phenyl-4-piperidinamine

The title compound is obtained in an analogous manner as in Example 10bstarting from 3,5-dichlorobenzoyl chloride; melting point 161°-163°; TLC(dichloromethane/methanol/25% strength ammonia solution;90:9.5:0:5):R_(f) =0.55.

EXAMPLE 96(2R*,4S*)-1-(1-Naphthoyl)-2-phenyl-N-(4-quinolylmethyl)-4-piperidineamine

The title compound of the formula ##STR114## is obtained in an analogousexample as described in Example 11; TLC (dichloromethane/methanol/25%strength ammonia solution, 90:9.5:0:5):R_(f) =0.41; FD-MS:M+=471

The starting material is obtained as follows:

a) (2R*,4S*)-N-Acetyl-1-(1-naphthoyl)-2-phenyl-4-piperidinamine

The title compound is obtained in an analogous manner as described inExample 10b; TLC (dichloromethane/methanol/25% strength ammoniasolution, 90:9.5:0:5):R_(f) =0.42.

EXAMPLE 97(2R*,4S*)-1-(3,5-Dimethylbenzoyl)-2-(1-naphthyl)-N-(4-quinolylmethyl)-4-piperidinamine

The title compound of the formula ##STR115## is obtained in an analogousmanner as described in Example 10; TLC (dichloromethane/methanol/25%strength ammonia solution, 90:9.5:0:5):R_(f) =0.50 FD-MS:M+=499

The starting material is obtained as follows:

a)(2R*,45*)-N-Acetyl-1-benzyloxycarbonyl-2-(1-naphthyl)-4-piperidinamine

The title compound is obtained in an analogous manner as described inExample 10a starting from naphthalene-1-carboxaldehyde in place ofbenzaldehyde; (dichloromethane/methanol/25% strength ammonia solution,90:9.5:0:5):R_(f) =0.31 FD-MS:M+=402.

b)(2R*,4S*)-(N)-Acetyl-1-(3,5-dimethylbenzoyl)-2-(1-naphthyl)-4-piperidinamine

The title compound is obtained in an analogous manner as described inExample 10b; TLC (dichloromethane/methanol/25% strength ammoniasolution, 90:9.5:0:5):R_(f) =0.26 FD-MS:M+=400.

EXAMPLE 98

The following compounds can also be prepared in an analogous manner asdescribed in Examples 85 to 97:

(2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(2-naphthyl)-N-(4-quinolinylmethyl)-4-piperidinamine;

(2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(4-methoxyphenylmethyl)-N-(4-quinolinylmethyl)-4-piperidinamine;

(2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(3-methoxyphenylmethyl)-N-(4-quinolinylmethyl)-4-piperidinamine;

(2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(4-nitrobenzyl)-N-(4-quinolinylmethyl)-4-piperidinamine;

(2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(4-trifluoromethylphenylmethyl)-N-(4-quinolinylmethyl)-4-piperidinamine;

(2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(2,4-dichlorophenylmethyl)-N-(4-quinolinylmethyl)-4-piperidinamine;

(2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(2-phenylethyl)-N-(4-quinolinylmethyl)-4-piperidinamine;

(2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(2-phenylethenyl)-N-(4-quinolinylmethyl)-4-piperidinamine;

(2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-benzoyl-N-(4-quinolinylmethyl)-4-piperidinamine;

(2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(4-chlorobenzoyl)-N-(4-quinolinylmethyl)-4-piperidinamine;

(2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(2-naphthyl)-N-(4-quinolinylmethyl)-4-piperidinamine;

(2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(4-methoxybenzyl)-N-(4-quinolinylmethyl)-4-piperidinamine;

(2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(3-methoxybenzyl)-(4-quinolinylmethyl)-4-piperidinamine;

(2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(4-nitrobenzyl)-(4-quinolinylmethyl)-4-piperidinamine;

(2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(4-trifluoromethylbenzyl)-(4-quinolinylmethyl)-4-piperidinamine;

(2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(2,4-dichlorobenzyl)-(4-quinolinylmethyl)-4-piperidinamine;

(2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(2-phenylethyl)-(4-quinolinylmethyl)-4-piperidinamine;

(2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(2-phenylethenyl)-N-(4-quinolinylmethyl)-4-piperidinamine;

(2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(benzoylmethyl)-N-(4-quinolinylmethyl)-4-piperidinamine;

(2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(4-chlorobenzoylmethyl)-N-(4-quinolinylmethyl)-4-piperidinamine.

EXAMPLE 99

Tables each containing 50 mg of(2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(2-phenethyl)-4-piperidinamineor a salt, for example the hydrochloride, thereof can be prepared asfollows:

    ______________________________________                                        Composition (10,000 tablets)                                                  ______________________________________                                        Active substance         500.0 g                                              Lactose                  500.0 g                                              Potato starch            352.0 g                                              Gelatin                  8.0 g                                                Talc                     60.0 g                                               Magnesium stearate       10.0 g                                               Silicon dioxide (highly disperse)                                                                      20.0 g                                               Ethanol                  q.s.                                                 ______________________________________                                    

The active substance is mixed with the lactose and 292 g of potatostarch, the mixture is moistened with an ethanolic solution of thegelatin and granulated through a screen. After drying, the remainder ofthe potato starch, the magnesium stearate, the talc and the silicondioxide are mixed in, and the mixture is compressed to tablets eachweighing 145.0 mg and containing 50.0 mg of active substance, which can,if required, be provided with dividing grooves for more accurateadaptation of the dosage.

Example 100

Lacquered tablets each containing 100 mg of(2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(2-phenethyl)4-piperidinamineor a salt, for example hydrochloride, thereof can be prepared asfollows:

    ______________________________________                                        Composition (for 1000 lacquered tablets)                                      ______________________________________                                        Active substance         100.0 g                                              Lactose                  100.0 g                                              Maize starch             70.0 g                                               Talc                     8.5 g                                                Calcium stearate         1.5 g                                                Hydroxypropylmethylcellulose                                                                           2.36 g                                               Shellac                  0.64 g                                               Water                    q.s.                                                 Methylene chloride       q.s.                                                 ______________________________________                                    

The active substance, the lactose and 40 g of the maize starch are mixedand moistened with a paste prepared from 15 g of maize starch and water(with heating) and granulated. The granules are dried, the remainder ofthe maize starch, the talc and the calcium stearate are added and mixedwith the granules. The mixture is compressed to tablets (weight:280 mg)and these are lacquered with a solution of hydroxypropylmethylcelluloseand of shellac in methylene chloride; final weight of the lacqueredtablet:283 mg.

EXAMPLE 101

Gelatin two-piece capsules containing 100 mg of active substance, forexample(2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(2-phenethyl)-4-piperidinamineor a salt, for example the hydrochloride, thereof can be prepared, forexample, as follows:

    ______________________________________                                        Composition (for 1000 capsules)                                               ______________________________________                                        Active substance        100.0 g                                               Lactose                 250.0 g                                               Microcrystalline cellulose                                                                            30.0 g                                                Sodium lauryl sulfate   2.0 g                                                 Magnesium stearate      8.0 g                                                 ______________________________________                                    

The sodium lauryl sulfate is screened in through a screen with a meshwidth of 0.2 mm into the lyophilised active substance. The twocomponents are intimately mixed. Then first the lactose is screened inthrough a screen with a mesh width of 0.6 mm and then themicrocrystalline cellulose is screened in through a screen with a meshwidth of 0.9 mm. This is followed by renewed intimate mixing for 10minutes. Finally, the magnesium stearate is screened in through a screenwith a mesh width of 0.8 mm. After mixing for a further 3 minutes, theresulting formulation is packed in 390 mg portions into size 0 gelatintwo-piece capsules.

EXAMPLE 102

It is also possible to prepare pharmaceutical products containinganother compound of the formula I according to one of the precedingpreparation examples in an analogous manner as described in previousExamples 99 to 101.

We claim:
 1. A 1-acylpiperidine compound of the formula I ##STR116## in which R₁ is an optionally substituted aralkyl, aryloxyalkyl, heteroaralkyl, aroyl, heteroaroyl, cycloalkylcarbonyl, aralkanoyl, heteroarylalkanoyl, aralkoxycarbonyl or arylcarbamoyl radical or the acyl radical of an α-amino acid which is optionally N-substituted by lower alkanoyl or carbamoyl-lower-alkanoyl, R₂ is cycloalkyl or an optionally substituted aryl or heteroaryl radical, R₃ is hydrogen, alkyl, carbamoyl or an alkanoyl or alkenoyl radical which is optionally substituted by carboxyl or esterified or amidated carboxyl, R₄ is an optionally substituted aryl or optionally partially hydrogenated heteroaryl radical, X₁ is methylene, ethylene, a direct linkage, an optionally ketalised carbonyl group or an optionally etherified hydroxymethylene group, X₂ is alkylene, carbonyl or a direct linkage, and X₃ is carbonyl, oxo-lower-alkylene, oxo(aza)-lower-alkylene or an alkylene radical which is optionally substituted by phenyl, hydroxymethyl, optionally esterified or amidated carboxyl or, in higher than the α position, by hydroxyl, or a salt thereof.
 2. A compound according to claim 1 of the formula I in which R₁ is a phenyl-, diphenylnaphthyl- or fluorenyl-lower-alkyl radical which is unsubstituted or substituted in the phenyl moiety by lower alkyl, lower alkoxy, di-lower-alkylamino, halogen and/or trifluoromethyl, a phenoxy-lower-alkyl radical which is unsubstituted or substituted in the phenyl moiety by halogen and/or triazolyl, a heteroaryl-lower-alkyl radical which has as heteroaryl radical aza-heteroaryl which is 6-membered and monocyclic or is bicyclic and composed of a 6-membered and a 5- or 6-membered ring, a benzoyl, naphthoyl fluorenoyl or 3- to 8-membered cycloalkylcarbonyl radical which is unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxyl, di-lower-alkylamino, halogen, cyano and/or trifluoromethyl, a phenyl- or diphenyl-lower-alkanoyl radical which is unsubstituted or substituted in the phenyl moiety by lower alkyl, lower alkoxy, di-lower-alkylamino, halogen and/or trifluoromethyl, a heteroaryl-lower-alkanoyl radical which has as heteroaryl radical aza-heteroaryl which is 6-membered and monocyclic or is bi- or tricyclic and composed of a 6-membered and one or two 5- or 6-membered ring(s), a phenyl-lower-alkoxycarbonyl or N-phenylcarbamoyl radical which is unsubstituted or substituted in the phenyl moiety by lower alkyl, lower alkoxy, di-lower-alkylamino, halogen and/or trifluoromethyl, or the acyl radical of an α-amino acid which occurs in nature as peptide building block and is optionally N-substituted by lower alkanoyl or carbarnoyl-lower-alkanoyl, R₂ is 5- to 7-membered cycloalkyl or a phenyl, naphthyl or 6-membered monocyclic aza-heteroaryl radical which is unsubstituted or substituted by aromatically bonded lower alkyl, lower alkoxy, halogen and/or trifluoromethyl, R₃ is hydrogen, lower alkyl, carbamoyl, lower alkanoyl, carboxy-lower-alkanoyl or carboxy-lower-alkenoyl, lower alkoxycarbonyl-lower-alkyl, carbamoyl-lower-alkanoyl, N-mono- or N,N-di-lower-alkylcarbamoyl-lower-alkanoyl, N-cyclalkylcarbamoyl-lower-alkanoyl or N-phenylcarbamoyl-lower-alkanoyl, R₄ is a phenyl, naphthyl or pyridyl radical which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen and/or trifluoromethyl, or a heteroaryl radical which is unsubstituted or C-substituted by lower alkyl, lower alkoxy, halogen and/or trifluoromethyl and optionally N-substituted by lower alkanoyl and is composed of an optionally partially hydrogenated 5- or 6-membered mono- or diaza- or oxa-heteroaryl radical and a 6-membered aryl radical, X₁ is methylene, ethylene, a carbonyl group which is optionally ketalised with a lower alkanol or a lower alkanediol, a hydroxymethylene group which is optionally etherified with a lower alkanol, or a direct linkage, X₂ is carbonyl, lower alkylene or a direct linkage, and X₃ is carbonyl, oxo-lower-alkylene, oxo(aza)-lower-alkylene or a lower alkylene radical which is unsubstituted or substituted by phenyl or in the 1, 2 or, where present, 3 position with respect to the N atom by carboxyl, lower alkoxycarbonyl, carbamoyl, N-mono- or N,N-di-lower-alkylcarbamoyl or hydroxymethyl, or a salt thereof.
 3. A compound according to claim 1 of the formula I in which R₁ is phenyl- or diphenyl-C₁ -C₄ alkyl which is unsubstituted or substituted in the phenyl moiety by lower alkyl, lower alkoxy, di-lower-alkylamino, halogen and/or trifluoromethyl, phenoxy-C₁ -C₄ alkyl which is unsubstituted or substituted in the phenyl moiety by halogen, and/or triazolyl, pyridyl- or quinolinyl-C₁ -C₄ alkyl, benzoyl which is unsubstituted or substituted by lower alkyl, lower alkoxy, naphthoyl which is unsubstituted or substituted by lower alkyl, lower alkoxy, di-lower-alkylamino, halogen and/or trifluoromethyl, pyridylcarbonyl or quinolinylcarbonyl which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen and/or trifluoromethyl, 5- to 7-membered cycloalkylcarbonyl which is unsubstituted or substituted by lower alkyl, lower alkoxy, di-lower-alkylamino, halogen and/or trifluoromethyl, phenyl- or diphenyl-C₁ -C₄ alkanoyl which is unsubstituted or optionally substituted in the phenyl by lower alkyl, lower alkoxy, di-lower-alkylamino, halogen and/or trifluoromethyl, N-phenylcarbamoyl which is unsubstituted or substituted in the phenyl moiety by lower alkyl, lower alkoxy, di-lower-alkylamino, halogen and/or trifluoromethyl, or a group of the formula Ia ##STR117## in which R₅ is hydrogen, C₁ -C₄ alkyl which is unsubstituted or substituted by hydroxyl, mercapto, amino, optionally hydroxy-substituted phenyl, carboxyl, carbamoyl or ureido, and R₆ is C₂ -C₇ alkanoyl, R₂ is 5- to 7-membered cycloalkyl or a phenyl, naphthyl or pyridyl radical which is unsubstituted or substituted by aromatically bonded C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halogen and/or trifluoromethyl, R₃ is hydrogen, C₁ -C₇ alkyl, carbamoyl, C₂ -C₇ alkanoyl, carboxy-C₁ -C₄ alkanoyl or carboxy-C₂ -C₄ alkenoyl, R₄ is phenyl or naphthyl which is unsubstituted or substituted by C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halogen and/or trifluoromethyl, or unsubstituted pyridyl, benzofuranyl, indolyl, 2,3-dihydroindolyl, benzimidazolyl, quinolyl or 1,2,3,4-tetrahydroquinolinyl, X₁ is methylene, hydroxymethylene, C₁ -C₄ alkoxymethylene, carbonyl, di-C₁ -C₄ alkoxymethylene or a direct linkage, X₂ is C₁ -C₇ alkylene, carbonyl or a direct linkage, and X₃ is carbonyl, C₁ -C₄ alkylene, carboxy-C₁ -C₄ alkylene, C₁ -C₄ alkoxycarbonyl-C1-C4alkylene, carbamoyl-C₁ -C₄ alkylene or hydroxymethyl-C₁ -C₄ alkylene, or a salt thereof.
 4. A compound claimed in claim 1 being (2R,4S)- or (2R,4R)2-benzyl-1-(3,5-dimethylbenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine or a salt thereof.
 5. A compound as claimed in claim 1 selected from(2R*,4S*)-2-benzyl-1-(2-naphthoyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3-trifluoromethylbenzoyl)-N-(4-quinolylmethyl)4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-(4-quinolylmethyl)4-piperidinamine; (2R*,4S*)-2-benzyl-1-(1-naphthoyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(2-quinolinylcarbonyl)-N-(4-quinolylmethyl)4-piperidinamine; (2R*,4S*)-2-benzyl-1-(4-chloro-phenylacetyl)-N-(4-quinolylmethyl)4-piperidinamine; (2R*,4S*)-2-benzyl-1-(benzyloxycarbonyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(2-phenylethyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(2-naphtylacetyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(4-quinolylmethyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(2,4-dichlorobenzyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(2,2-diphenylethyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(phenylcarbamoyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(diphenylacetyl)-N-(4-quinolylmethyl)-4-piperidinamine (2R*,4S*)-2-benzyl-1-(2-pyridylacetyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(4-pyridylacetyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(2,3-diphenylpropionyl)-N-(4-quinolylmethyl)4-piperidinamine; (2R*,4S*)-2-benzyl-1-((3S)-(2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-3-yl)-carbonyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3-methoxybenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3-N,N-dimethylaminobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(cis,cis-3,5-dimethylcyclohexylcarbonyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3,5-bis-(trifluoromethyl)-benzyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2S*,4R*)-2-benzyl-1-[2-(5-chloro-1H-1,2,4-triazol-1-yl)phenoxyethyl]-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-((S)-phenylalanyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-((R)-phenylalanyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-((S)-N-acetyl-phenylalanyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-((R)-N-acetyl-phenylalanyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-((S)-N-(4-carboxamido-butyroyl)-phenylalanyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-((R)-N-(4-carboxamido-butyroyl)-phenylalanyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-benzoyl-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3-chlorobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylmethyl)-N-(3-carboxamido-propionyl)-4-piperidinamine; (2R,4S)-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylmethyl)-N-(3-carboxamido-propionyl)-4-piperidinamine; (2S,4R)- and (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(2-phenethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(3-quinolylmethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(2-quinolylmethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(2-quinolylmethyl)-4-piperidinamine; (2R,4S)- and (2R,4R)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-benzyl-4-piperidinamine; (2S,4R)- and (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-benzyl-4-piperidinamine; (2R,4S)- and (2R,4R)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(4-pyridylmethyl)-4-piperidinamine; (2R,4S)- and (2R,4R)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(3-pyridylmethyl)-4-piperidinamine; (2S,4R)- and (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R,4S)- and (2R,4R)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(2-phenethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-bis-(trifluoromethyl)-benzoyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(2,4-dichlorobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(phenylacetyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(2,6-dichlorobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3,5-dibromobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(9-fluorenoyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3-toluoyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3-bromobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3,5-dihydroxybenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3-cyanobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(2-chlorobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(4-chlorobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(9-fluorenyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylmethyl)-N-methyl-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylmethyl)-N-cyclohexylcarbamoy-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylmethyl)-N-phenylcarbamoy-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(2-phenylethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3,5-bis-(trifluoromethyl)-benzoyl)-N-(2-phenylethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(2-naphthoyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(3,5-dimethylbenzoyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylcarbonyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(3-indolylcarbonyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(2-indolylcarbonyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(5-methoxy-2-indolylcarbonyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(1-naphthoyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(phenylacetyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(2-methoxybenzyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(3-(N-acetyl)-indolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(2-benzo[b]furanylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-[(3-methylbenzo[b]thiophen-2-ylmethyl]-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(5-methoxyindol-3-ylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(3-indolylmethyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-phenylcarbamoyl-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-diphenylmethyl-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(3,4-dihydro-2H-1-benzopyran-2-carbonyl)-4-piperidinamine; (2R*,4S*)-2-benzyl-1-(4-methoxybenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine; (2R*,4S*,1'R*)-N-benzyl-1-(3,5-dimethylbenzoyl)-2-(1'-hydroxy-1'-phenyl-methyl)-4-piperidinamine; (2R*,4S*,1'R*)-2-(1'-hydroxy-1'-phenyl-methyl)-1-(3,5-dimethylbenzoyl)-N-(4-quinolinylmethyl)-4-piperidinamine; (2R*,4S*,1'S*)-1-(3,5-dimethylbenzoyl)-2-(1'-hydroxy-1'-phenyl-methyl)-N-(4-quinolinylmethyl)-4-piperidinamine; (2R*,4S*,1'R*)-2-{1'-hydroxy-1'-(4-chlorophenyl)methyl}-1-(3,5-dimethylbenzoyl)-N-(4-quinolinylmethyl)-4-piperidinamine; (2R*,4S*,1'S*)-1-(3,5-dimethylbenzoyl)-2-{1'-hydroxy-1'-(4-chlorophenyl)-methyl}-N-(4-quinolinylmethyl)-4-piperidinamine; (2R*,4S*,1'S*)-1-(3,5-dimethylbenzoyl)-2-{1'-hydroxy-1'-(3,4-dichlorophenyl)-methyl}-N-(4-quinolinylmethyl)-4-piperidinamine; (2R*,4S*,)-N-benzyl-1-(3,5-dimethylbenzoyl)-2-benzoyl-4-piperidinamine; (2R*,4S*)-2-(4-Chlorobenzyl)-1-(3,5-dimethylbenzoyl)-N-(4-quinolinylmethyl)-4-piperidinamine; (2R*,4S*)-2-(3,4-dichlorobenzyl)-1-(3,5-dimethylbenzoyl)-N-(4-quinolinylmethyl)-4-piperidinamine; (2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-phenyl-N-(4-quinolinylmethyl)-4-piperidinamine; (2R*,4S*)-1-(3,5-dichlorobenzoyl)-2-phenyl-N-(4-quinolinmmthyl)-4-piperidinamine; (2R*,4S*)-1-(1-Naphthoyl)-2-phenyl-N-(4-quinolinylmethyl)-4-piperidineamine and (2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(1-naphthyl)-N-(4-quinolinylmethyl)-4-piperidinamine and, in each case, of a pharmaceutically acceptable salt thereof.
 6. A compound as claimed in claim 1 selected from(2R*,4S*)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-benzyl-N-carbamoyl-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(3-phenylpropyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(3-phenylpropyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(2-methoxybenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(2-methoxybenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2-methoxyphenyl)ethyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2-methoxyphenyl)ethyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2-methoxyphenyl)propyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2-methoxyphenyl)propyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(2-trifluoromethylbenzyl)-4-piperidinamine: (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(2-trifluoromethylbenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2-trifluoromethylphenyl)ethyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2-trifluoromethylphenyl)ethyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2-trifluoromethylphenyl)propyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2-trifluoromethylphenyl)propyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(3-trifluoromethylbenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(3-trifluoromethylbenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(3-trifluoromethylphenyl)ethyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(3-trifluoromethylphenyl)ethyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(3-trifluoromethylphenyl)propyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(3-trifluoromethylphenyl)propyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(4-trifluoromethylbenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(4-trifluoromethylbenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(4-trifluoromethylphenyl)ethyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(4-trifluoromethylphenyl)ethyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(4-trifluoromethylphenyl)propyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(4-trifluoromethylphenyl)propyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(2,3-dimethoxybenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(2,3-dimethoxybenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2,3-dimethoxyphenyl)ethyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2,3-dimethoxyphenyl)ethyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2,3-dimethoxyphenyl)propyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2,3-dimethoxyphenyl)propyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(2,4-dimethoxybenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(2,4-dimethoxybenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2,4-dimethoxyphenyl)ethyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2,4-dimethoxyphenyl)ethyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2,4-dimethoxyphenyl)propyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2,4-dimethoxyphenyl)propyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(2,5-dimethoxybenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(2,5-dimethoxybenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2,5-dimethoxyphenyl)ethyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2,5-dimethoxyphenyl)ethyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2,5-dimethoxyphenyl)propyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2,5-dimethoxyphenyl)propyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(2,6-dimethoxybenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(2,6-dimethoxybenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2,6-dimethoxyphenyl)ethyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2,6-dimethoxyphenyl)ethyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2,6-dimethoxyphenyl)propyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2,6-dimethoxyphenyl)propyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(2,3-methylenedioxybenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(2,3-methylenedioxybenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2,3-methylenedioxyphenyl)ethyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2,3-methylenedioxyphenyl)ethyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2,3-methylenedioxyphenyl)propyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2,3-methylenedioxyphenyl)propyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(2,4-methylenedioxybenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(2,4-methylenedioxybenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2,4-methylenedioxyphenyl)ethyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2,4-methylenedioxyphenyl)ethyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2,4-methylenedioxyphenyl)propyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2,4-methylenedioxyphenyl)propyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(indol-2-ylmethyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(indol-2-ylmethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(indol-3-ylmethyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(indol-3-ylmethyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(quinolin-2-ylmethyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(quinolin-3-ylmethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5 -dimethylbenzoyl)-N-(2-chlorobenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(2-chlorobenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2-chlorophenyl)ethyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2-chlorophenyl)ethyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2-chlorophenyl)propyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2-chlorophenyl)propyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(3-chlorobenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(3-chlorobenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(3-chlorophenyl)ethyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(3-chlorophenyl)ethyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(3-chlorophenyl)propyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(3-chlorophenyl)propyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(4-chlorobenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(4-chlorobenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(4-chlorophenyl)ethyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(4-chlorophenyl)ethyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(4-chlorophenyl)propyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(4-chlorophenyl)propyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(4-methoxynaphth-1-ylmethyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(4-methoxynaphth-1-ylmethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(3,4-ethylenedioxybenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(3,4-ethylenedioxybenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(indol-2-ylmethyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(indol-2-ylmethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(indol-3-ylmethyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(indol-3-ylmethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(quinolin-2-ylmethyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(quinolin-2-ylmethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(quinolin-3-ylmethyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(quinolin-3-ylmethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(2-chlorobenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(2-chlorobenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2-chlorophenyl)ethyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2-chlorophenyl)ethyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2-chlorophenyl)propyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2-chlorophenyl)propyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(3-chlorobenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(3-chlorobenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(3-chlorophenyl)ethyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(3-chlorophenyl)ethyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(3-chlorophenyl)propyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(3-chlorophenyl)propyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(4-chlorobenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(4-chlorobenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(4-chlorophenyl)ethyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(4-chlorophenyl)ethyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(4-chlorophenyl)propyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(4-chlorophenyl)propyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(4-methoxynaphth-1-ylmethyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(4-methoxynaphth-1-ylmethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(3,4-ethylenedioxybenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(3,4-ethylenedioxybenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(indol-2-ylmethyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(indol-2-ylmethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(indol-3-ylmethyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(indol-3-ylmethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(quinolin-2-ylmethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(quinolin-3-ylmethyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(quinolin-3-ylmethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(2-chlorobenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(2-chlorobenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2-chlorophenyl)ethyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(2-chlorophenyl)ethyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2-chlorophenyl)propyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(2-chlorophenyl)propyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(3-chlorobenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(3-chlorobenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(3-chlorophenyl)ethyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(3-chlorophenyl)ethyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(3-chlorophenyl)propyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(3-chlorophenyl)propyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(4-chlorobenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(4-chlorobenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(4-chlorophenyl)ethyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[2-(4-chlorophenyl)ethyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(4-chlorophenyl)propyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[3-(4-chlorophenyl)propyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(4-methoxynaphth-1-ylmethyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(4-methoxynaphth-1-ylmethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(3,4-ethylenedioxybenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(3,4-ethylenedioxybenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(indol-2-ylmethyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(indol-2-ylmethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(indol-3-ylmethyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(indol-3-ylmethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(quinolin-2-ylmethyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(quinolin-2-ylmethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(quinolin-3-ylmethyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(quinolin-3-ylmethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(2-chlorobenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(2-chlorobenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-[2-(2-chlorophenyl)ethyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-[2-(2-chlorophenyl)ethyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-[3-(2-chlorophenyl)propyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-[3-(2-chlorophenyl)propyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(3-chlorobenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(3-chlorobenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-[2-(3-chlorophenyl)ethyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-[2-(3-chlorophenyl)ethyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-[3-(3-chlorophenyl)propyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-[3-(3-chlorophenyl)propyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(4-chlorobenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(4-chlorobenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-[2-(4-chlorophenyl)ethyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-[2-(4-chlorophenyl)ethyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-[3-(4-chlorophenyl)propyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-[3-(4-chlorophenyl)propyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(4-methoxynaphth-1-ylmethyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(4-methoxynaphth-1-ylmethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-ditrifluoromethylbenzoyl)-N-(3,4-ethylenedioxybenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-ditrifluormethylbenzoyl)-N-(3,4-ethylenedioxybenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(indol-2-ylmethyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(indol-2-ylmethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(indol-3-ylmethyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(indol-3-ylmethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(quinolin-2-ylmethyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(quinolin-2-ylmethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(quinolin-3-ylmethyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(quinolin-3-ylmethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(2-chlorobenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(2-chlorobenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-[2-(2-chlorophenyl)ethyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-[2-(2-chlorophenyl)ethyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-[3-(2-chlorophenyl)propyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-[3-(2-chlorophenyl)propyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(3-chlorobenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(3-chlorobenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-[2-(3-chlorophenyl)ethyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-[2-(3-chlorophenyl)ethyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-[3-(3-chlorophenyl)propyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-[3-(3-chlorophenyl)propyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-chlorobenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-chlorobenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-[2-(4-chlorophenyl)ethyl]-4-piperidinamine: (2S,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-[2-(4-chlorophenyl)ethyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-[3-(4-chlorophenyl)propyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-[3-(4-chlorophenyl)propyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-methoxynaphth-1-ylmethyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-methoxynaphth-1-ylmethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(3,4-ethylenedioxybenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(3,4-ethylenedioxybenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-(indol-2-ylmethyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-(indol-2-ylmethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-(indol-3-ylmethyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-(indol-3-ylmethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-(quinolin-2-ylmethyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-(quinolin-2-ylmethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-(quinolin-3-ylmethyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-(quinolin-3-ylmethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-(2-chlorobenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-(2-chlorobenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-[2-(2-chlorophenyl)ethyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-[2-(2-chlorophenyl)ethyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-[3-(2-chlorophenyl)propyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-[3-(2-chlorophenyl)propyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-(3-chlorobenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-(3-chlorobenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-[2-(3-chlorophenyl)ethyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-[2-(3-chlorophenyl)ethyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-[3-(3-chlorophenyl)propyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-[3-(3-chlorophenyl)propyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-(4-chlorobenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-(4-chlorobenzyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-[2-(4-chlorophenyl)ethyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-[2-(4-chlorophenyl)ethyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-[3-(4-chlorophenyl)propyl]-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-[3-(4-chlorophenyl)propyl]-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-(4-methoxynaphth-1-ylmethyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-(4-methoxynaphth-1-ylmethyl)-4-piperidinamine; (2R,4S)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-(3,4-ethylenedioxybenzyl)-4-piperidinamine; (2S,4S)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-(3,4-ethylenedioxybenzyl)-4-piperidinamine; (2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(2-naphthyl)-N-(4-quinolinylmethyl)-4-piperidinamine; (2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(4-methoxyphenylmethyl)-N-(4-quinolinylmethyl)-4-piperidinamine; (2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(3-methoxyphenylmethyl)-N-(4-quinolinylmethyl)-4-piperidinamine; (2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(4-nitrobenzyl)-N-(4-quinolinylmethyl)-4-piperidinamine; (2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(4-trifluoromethylphenylmethyl)-N-(4-quinolinylmethyl)-4-piperidinamine; (2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(2,4-dichlorophenylmethyl)-N-(4-quinolinylmethyl)-4-piperidinamine; (2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(2-phenylethyl)-N-(4-quinolinylmethyl)-4-piperidinamine; (2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(2-phenylethenyl)-N-(4-quinolinylmethyl)-4-piperidinamine; (2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-benzoyl-N-(4-quinolinylmethyl)-4-piperidinamine; (2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(4-chlorobenzoyl)-N-(4-quinolinylmethyl)-4-piperidinamine; (2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(2-naphthyl)-N-(4-quinolinylmethyl)-4-piperidinamine; (2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(4-methoxybenzyl)-N-(4-quinolinylmethyl)-4-piperidinamine; (2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(3-methoxybenzyl)-(4-quinolinylmethyl)-4-piperidinamine; (2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(4-nitrobenzyl)-(4-quinolinylmethyl)-4-piperidinamine; (2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(4-trifluoromethylbenzyl)-(4-quinolinylmethyl)-4-piperidinamine; (2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(2,4-dichlorobenzyl)-(4-quinolinylmethyl)-4-piperidinamine; (2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(2-phenylethyl)-(4-quinolinylmethyl)-4-piperidinamine; (2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(2-phenylethenyl)-N-(4-quinolinylmethyl)-4-piperidinamine; (2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(benzoylmethyl)-N-(4-quinolinylmethyl)-4-piperidinamine and (2R*,4S*)-1-(3,5-dimethylbenzoyl)-2-(4-chlorobenzoylmethyl)-N-(4-quinolinylmethyl)-4-piperidinamine and, in each case, a pharmaceutically acceptable salt thereof.
 7. A pharmaceutical composition comprising a compound according to claim 1 in free form or in pharmaceutically acceptable salt form in admixture to customary pharmaceutical auxiliary substances.
 8. Method for the treatment of disorders in whose development substance P plays an essential part, characterised in that a compound according to claim 1 or a pharmaceutically acceptable salt thereof is administered to a warm-blooded animal requiring such treatment. 